Heteroaryl compounds and their use as therapeutic drugs

ABSTRACT

The present invention provides heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt, which are capable of modulating the activity of Mer receptor tyrosine kinase (MERTK). This invention also provides pharmaceutical compositions thereof, methods to prepare the said compounds, and the use of such compounds as a medicament. 
     The present invention is directed to MERTK inhibitory compounds with marked potency, thereby having an outstanding potential for a pharmaceutical intervention of cancer and any other diseases related to MERTK dysregulation.

RELATED APPLICATION

This application claims the benefit of priority under U.S.C. §119(e) toU.S. Provisional Patent Application Ser. No. 62/212,520 filed Aug. 31,2015, which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel heterocyclic compounds having Merkinase inhibitory activity, a stereoisomer thereof, an enantiomerthereof, or a pharmaceutically acceptable salt thereof, the use forpreparing pharmaceutical compositions, pharmaceutical compositionscomprising the same, methods of treating diseases using thesecompositions.

BACKGROUND ART

Transmembrane receptor tyrosine kinases (RTKs) comprise anevolutionarily conserved family of structurally related proteins. Thegene Mer is a member of the Tyro3/Axl/Mer (TAM) receptor kinase familyand a proto-oncogene. Its abnormal expression and activation is found inconjunction with human cancers such as pituitary adenomas, mantle celllymphomas, and T-cell acute lymphoblastic leukemia.

The ATP-binding site is similar for all protein kinases. For thisreason, it is challenging to find an inhibitor that is specific for theMer. Compound-52, a 2,6,9-trisubstituted purine that occupies theATP-binding site, was actually the first molecule that was found to besuccessful in inhibiting Mer (J Struct Biol. 2009 February; 165(2):88-96). This inhibitor has, however, limited potency and lack ofselectivity. Lately, several compounds have been unveiled mostly bymodifying Compound-52 including UNC-569, UNC-1062, and UNC-2025 (ACS MedChem Lett. 2012 Feb. 9; 3(2):129-134, Eur J Med Chem. 2013 July;65:83-93, J Med Chem. 2014 Aug. 28; 57(16):7031-41).

It is an object of the invention to provide reagents and methods ofregulating a receptor tyrosine kinase Mer. This and other objects of theinvention are provided by one or more of the embodiments describedbelow.

DISCLOSURE Technical Problem

Several Mer kinase inhibitors have been previously described, but theyhave different moieties onto the scaffold from the present invention.Highly potent and selective Mer kinase inhibitors based on aminopyridineor aminopyrimidine scaffolds are described.

The present invention relates to compounds capable of inhibiting theactivity of Mer, which compounds are useful for the prevention and/orthe treatment of cancer and other immune-related diseases such asinfection and sepsis.

Technical Solution Novel Mer Kinase Inhibitors

The present invention relates to a heterocyclic compound represented bythe following Formula I, a stereoisomer thereof, an enantiomer thereof,or a pharmaceutically acceptable salt thereof:

wherein:

X is CR⁷, or N;

Y is CHR⁸, NR⁸, or O;

Z is CH₂, CH₂O, C(═O), C(═O)O, C(═O)NH, NR⁸, NHC(═O), O or O(C═O);

R¹ is H, halogen, C₁₋₃ alkyl, NHR⁸ or OR⁸;

R² is H, halogen, C₁₋₄ alkyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂alkylheterocyclyl or -L-aryl, which C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, C₁₋₂ alkylheterocyclyl or -L-aryl may optionally besubstituted with one or more R⁹;

R³ is H, halogen, CN, C₁₋₃ alkyl, cycloalkenyl, C₂₋₆ alkenyl, aryl,biaryl, heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl which aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl may optionally be substitutedwith one or more R⁹;

R⁴ and R⁵ each independently is H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₁₀cycloalkyl, C(═O) R⁶, C₁₋₂ alkylaryl, aryl; or

R⁴ and R⁵ may be combined with each other to form a 3-7 membered cyclicring or heterocyclic ring containing 1 or 2 of NR⁸, O or S, and thecyclic or heterocyclic ring may optionally be substituted with 1 or 2halogen(s), C₁₋₄ alkyl or C₁₋₄ alkoxy;

R^(5′) is H or R⁵ and R^(5′) may be combined with each other to formcarbonyl;

R⁶ is H, C₁₋₄ alkyl, C₁₋₆ alkoxy, —NR¹⁵R¹⁶, aryl, biaryl, heteroaryl,heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂alkylheterocyclyl, C₁₋₂ alkylbiaryl, -L-aryl or -L-biaryl, which C₁₋₄alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂ alkylheterocyclyl, C₁₋₂alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted withone or more R⁹;

R⁷ is H, halogen or C₁₋₃ alkyl;

R⁸ is H, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkylarylor C(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionally besubstituted with one or more R⁹;

when Z is NR⁸, R⁸ and R⁶ may be combined with each other to form a 3-7membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;

R⁹ is halogen, hydroxyl, —CN, —NO₂, —COOH, —(C═O)H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy,cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR¹⁵R¹⁶, -L-NR¹⁵R¹⁶,-L-COOR¹⁷, -L-alkyl, -L-C₃₋₁₀ cycloalkyl, -L-heterocyclyl,-L-heteroaryl, or -L-aryl which C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl,heterocyclyl, heteroaryl, -L-alkyl, -L-C₃₋₁₀ cycloalkyl,-L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen,hydroxyl, —CN, —NR¹⁵R¹⁶, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₄hydroxyalkyl, C₂₋₆ alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or—(CH₂)_(l)—C(═O)—NR¹⁵R¹⁶;

R¹⁰ is C₁₋₃ alkyl or C₁₋₃ alkylaryl;

R¹⁵ and R¹⁶ each independently is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl orSO₂R¹⁷;

R¹⁷ is H, C₁₋₃alkyl or C₁₋₃ alkylaryl;

L is C₁₋₃ alkyl, C₁₋₃ alkylO, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,—(CH₂)_(l)—C(═O)—(CH₂)_(m)—, C(═O)O, —(CH₂)_(l)—C(═O)NH—(CH₂)_(m)—,—(CH₂)_(l)—NHC(═O)—(CH₂)_(m)—, —(CH₂)_(l)—NH—(CH₂)_(m),—NH—C(═O)—CR¹⁵R¹⁶—NH—C(═O)—, NHC(═O), O, O(C═O)S, S(═O), or SO₂; and

l and m each independently is an integer of 0 to 2.

In accordance with a second embodiment of the present invention, thereare provided the heterocyclic compound represented formula I isrepresented by the following Formula Ia:

wherein:

X is CH, or N;

Y is NR⁸, or O;

W is CH₂, (CH₂)₂, NR¹¹, or O;

Z is CH₂, CH₂O, C(═O), C(═O)O, C(═O)NH, NR⁸, NHC(═O), O or O(C═O);

R³ is H, halogen, CN, C₁₋₃ alkyl, cycloalkenyl, C₂₋₆ alkenyl, aryl,biaryl, heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl which aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl may optionally be substitutedwith one or more R⁹,

R⁶ is H, C₁₋₄ alkyl, C₁₋₆ alkoxy, —NR¹⁵R¹⁶, aryl, biaryl, heteroaryl,heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂alkylheterocyclyl, C₁₋₂ alkylbiaryl, -L-aryl or -L-biaryl, which C₁₋₄alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂ alkylheterocyclyl, C₁₋₂alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted withone or more R⁹;

R⁸ is H, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkylarylor C(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionally besubstituted with one or more R⁹;

when Z is Me, R⁸ and R⁶ may be combined with each other to form a 3-7membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;

R⁹ is halogen, hydroxyl, —CN, —NO₂, —COOH, —(C═O)H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy,cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR¹⁵R¹⁶, -L-NR¹⁵R¹⁶,-L-COOR¹⁷, -L-alkyl, -L-C₃₋₁₀ cycloalkyl, -L-heterocyclyl,-L-heteroaryl, or -L-aryl which C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl,heterocyclyl, heteroaryl, -L-alkyl, -L-C₃₋₁₀ cycloalkyl,-L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen,hydroxyl, —CN, —NR¹⁵R¹⁶, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₄hydroxyalkyl, C₂₋₆ alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or—(CH₂)_(l)—C(═O)—NR¹⁵R¹⁶;

R¹⁰ is C₁₋₃ alkyl or C₁₋₃ alkylaryl;

R¹¹ is H, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃alkylaryl or C(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionallybe substituted with one or more R⁹;

R¹⁵ and R¹⁶ each independently is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl orSO₂R¹⁷;

R¹⁷ is H, C₁₋₃ alkyl or C₁₋₃ alkylaryl;

R¹⁸ to R²¹ are the same as or different from each other, and are eachindependently H or halogen; or

R¹⁸ and R¹⁹; or R²⁰ and R²¹ may be combined with each other to form a3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of Me, Oor S, and the cyclic or heterocyclic ring may optionally be substitutedwith 1 or 2 halogen(s), C₁₋₄ alkyl or C₁₋₄ alkoxy;

L is C₁₋₃ alkyl, C₁₋₃ alkylO, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,—(CH₂)_(l)—C(═O)—(CH₂)_(m)—, C(═O)O, —(CH₂)_(l)—C(═O)NH—(CH₂)_(m)—,—(CH₂)_(l)—NHC(═O)—(CH₂)_(m)—, —(CH₂)_(l)—NH—(CH₂)_(m)—, NR⁸,—NH—C(═O)—CR¹⁵R¹⁶—NH—C(═O)—NHC(═O)—, O, O(C═O)S, S, S(═O), or SO₂; and

l and m each independently is an integer of 0 to 2.

In accordance with a third embodiment of the present invention, thereare provided the heterocyclic compound represented formula I isrepresented by the following Formula Ib:

wherein:

X is CH, or N;

W is CH₂, NR¹¹, or O;

V¹ and V² each independently is CR¹³R^(13′), NR¹³ or O;

-   -   at least one of V₁ and V₂ is CR¹³R^(13′);

X¹ to X⁵ are the same as or different from each other, and are eachindependently CR¹⁴ or N;

at least one of X¹ to X⁵ is CR¹⁴;

R³ is H, halogen, CN, C₁₋₃ alkyl, cycloalkenyl, C₂₋₆ alkenyl, aryl,biaryl, heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl which aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl may optionally be substitutedwith one or more R⁹;

R⁹ is halogen, hydroxyl, —CN, —NO₂, —COOH, —(C═O)H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy,cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR¹⁵R¹⁶, -L-NR¹⁵R¹⁶,-L-COOR′⁷, -L-alkyl, -L-C₃₋₁₀ cycloalkyl, -L-heterocyclyl,-L-heteroaryl, or -L-aryl which C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl,heterocyclyl, heteroaryl, -L-alkyl, -L-C₃₋₁₀ cycloalkyl,-L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen,hydroxyl, —CN, —NR¹⁵R¹⁶, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₄hydroxyalkyl, C₂₋₆ alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or—(CH₂)_(l)—C(═O)—NR¹⁵R¹⁶;

R¹⁰ is C₁₋₃ alkyl or C₁₋₃ alkylaryl;

R¹¹ is H, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃alkylaryl or C(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionallybe substituted with one or more R⁹;

R¹³ and R^(13′) each independently is H, C₁₋₃ alkyl, C₂₋₃ hydroxyalkyl;

each R¹⁴ is independently selected from H, halogen, hydroxyl, —CN, —NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, cycloalkenyl,aryl, heterocyclyl, heteroaryl, —NR¹⁵R¹⁶, -L-alkyl, -L-heterocyclyl,-L-heteroaryl, or -L-aryl which C₁₋₆ alkyl, aryl, heteroaryl,heterocyclyl may optionally be substituted with one or more R⁹; oradjacent groups among a plurality of R¹⁴s are bonded to each other toform a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2of NR¹¹ O or S, and the cyclic or heterocyclic ring may optionally besubstituted with 1 or 2 halogen(s), C₁₋₄ alkyl or C₁₋₄ alkoxy;

R¹⁵ and R¹⁶ each independently is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl orSO₂R¹⁷;

R¹⁷ is H, C₁₋₃ alkyl or C₁₋₃ alkylaryl;

L is C₁₋₃ alkyl, C₁₋₃ alkylO, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,—(CH₂)_(l)—C(═O)—(CH₂)_(m)—, C(═O)O, —(CH₂)_(l)—C(═O)NH—(CH₂)_(m)—,—(CH₂)_(l)—NHC(═O)—(CH₂)_(m)—, —(CH₂)_(l)—NH—(CH₂)_(m), NR⁸,—NH—C(═O)—CR¹⁵R¹⁶—NH—C(═O)—, NHC(═O), O, O(C═O)S, S, S(═O), or SO₂; and

l and m each independently is an integer of 0 to 2.

In the present disclosure, a halogen may be fluorine, chlorine, bromineor iodine.

In the present disclosure, the alkyl may be straight or branched, andthe number of carbon atoms thereof is not particularly limited, but ispreferably 1 to 6. Specific examples thereof include a methyl group, anethyl group, a propyl group, an isopropyl group, a butyl group, a pentylgroup, a hexyl group, and the like, or a branched chain thereof, but arenot limited thereto.

In the present disclosure, the cycloalkyl is not particularly limited,but has preferably 3 to 10 carbon atoms. Specific examples thereofinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, a norbornyl group, an adamantly group, and the like, but arenot limited thereto.

In the present disclosure, the alkoxy may be straight, branched, orcyclic. The number of carbon atoms of the alkoxy group is notparticularly limited, but is preferably 1 to 6. Specific examplesthereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, and the like, but are not limited thereto.

In the present disclosure, the alkenyl may be straight or branched, andthe number of carbon atoms thereof is not particularly limited, but ispreferably 2 to 6. Specific examples thereof include vinyl, 1-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 3-methyl-1-butenyl, 1,3-butadienyl, and the like, but arenot limited thereto.

In the present disclosure, the aryl may be monocyclic, or polycyclic andthe number of carbon atoms is not particularly limited, but ispreferably 6 to 60. Specific examples of the aryl group include amonocyclic aromatic group, such as a phenyl group and a polycyclicaromatic group, such as a naphthyl group, an anthracenyl group, aphenanthrenyl group, a pyrenyl group, a perylenyl group, a tetracenylgroup, a chrysenyl group, a fluorenyl group, an acenaphthacenyl group, atriphenylene group, and a fluoranthene group, and the like, but are notlimited thereto.

In the present disclosure, the biaryl may two or more monocyclics and/orpolycyclics linked each other.

In the present disclosure, the aryl in the alkylaryl and biaryl is thesame as the above-described examples of the aryl group.

In the present disclosure, a heterocyclic or a heteroaryl including oneor more hetero atom, for example, a heterocyclic group including one ormore of O, N, S, Si, Se and the like. Examples of the heterocyclic groupinclude a thiophene group, a furan group, a pyrrole group, an imidazolegroup, a thiazole group, an oxazole group, an oxadiazole group, atriazole group, a pyridyl group, a bipyridyl group, a triazine group, anacridyl group, a pyridazine group, a pyrrolidine group, a morpholinegroup, a piperazin group, a piperidine group, a tetrahydrofuran group, apyrazole group, a quinolinyl group, an isoquinoline group, an indolegroup, a carbazole group, a benzoxazole group, a benzimidazole group, abenzothiazole group, a benzocarbazole group, a benzothiophene group, adibenzothiophene group, a benzofuranyl group, a phenanthroline group, adibenzofuranyl group, and the like, but are not limited thereto.

In the present disclosure, the “adjacent” group may mean a substituentsubstituted with an atom directly linked to an atom in which thecorresponding substituent is substituted, a substituent disposedsterically closest to the corresponding substituent, or anothersubstituent substituted with an atom in which the correspondingsubstituent is substituted. For example, two substituents substituted atthe ortho position in a benzene ring and two substituents substitutedwith the same carbon in an aliphatic ring may be interpreted as groups“adjacent” to each other.

In the present disclosure, the cyclic ring or heterocyclic ring formedby binding two or more R¹⁴s comprises cycloalkyl, cycloalkenyl, aryl,heterocycle, heteroaryl. In accordance with a forth embodiment of thepresent invention, there are provided the heterocyclic compoundrepresented formula I is represented by any one of the followingcompounds.

Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 22-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 32-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 42-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 52-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 62-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 72-amino-N-((1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 82-amino-N-((1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 92-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 102-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 112-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 122-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 132-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 142-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 152-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 162-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 172-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 182-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 192-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 202-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 212-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 222-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamide Example 232-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 242-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 252-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 262-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 272-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 282-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 292-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide Example 302-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamide Example 312-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 322-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 332-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 342-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 352-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 362-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 372-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 382-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamide Example 402-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 412-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamide Example 42 methyl3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate Example 432-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 442-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 452-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 462-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamid Example 472-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 482-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 492-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamide Example 512-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 522-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 532-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 542-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 55 methyl(3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoyl)glycinate Example 562-amino-N-((1S,2S)-2-((3-((2-hydroxyethyl)carbamoyl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 572-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)oxy)cyclopentyl)nicotinamide Example 582-amino-N-((1S,2S)-2-((3-((S)-2-aminopropanamido)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 59 N-((1S,2S)-2-((3-((S)-2-acetamidopropanamido)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 602-amino-N-((1S,2S)-2-((3-(3-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 61N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 62N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 632-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamide Example 642-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamide Example 652-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example66 N-(trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 67N-((1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 68N-((1S,2S)-2-([1,1′-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 692-amino-N-((1S,2S)-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 702-amino-N-(cis-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 71N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 72N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-((3,4-dimethylbenzyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 732-amino-N-((6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 742-amino-N-(trans-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 752-amino-N-((1S,2S)-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 762-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 772-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamide Example 782-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 792-amino-N-(trans-2,2-difluoro-5-(phenoxymethyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 802-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 81 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamide Example 822-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)methyl)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 832-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide Example 842-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamide Example 852-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 862-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentyl)nicotinamide Example 87(1S,2S)-2-(benzyloxy)cyclopentyl 2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinate Example 882-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamide Example 892-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 902-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-morpholinotetrahydrofuran-3-yl)nicotinamide Example 912-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)nicotinamide Example 922-amino-N-(cis-4-hydroxytetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 932-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 942-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 95(R)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 96(S)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 97(S)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 98(R)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 992-amino-N-(1-(benzyloxy)-2-methylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 100(R)-2-amino-N-(1-((3,4-dimethylbenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 101(S)-2-amino-N-(2-((3,4-dimethylbenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 102(R)-2-amino-N-(1-((4-chlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 103(S)-2-amino-N-(2-((4-chlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 104(R)-2-amino-N-(1-((3,4-dichlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 105(S)-2-amino-N-(2-((3,4-dichlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 106(R)-2-amino-N-(1-((3-methoxybenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 107(S)-2-amino-N-(2-((3-methoxybenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 108(R)-2-amino-N-(1-(benzyloxy)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 109(S)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 110(R)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 111(S)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 112(R)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 113(R)-2-amino-N-(2-(benzyloxy)-1-cyclohexylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 114(R)-2-amino-N-(1-cyclohexyl-2-hydroxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 115(S)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 116(R)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 117(S)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 118(R)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 119(R)-2-amino-N-(1-(cyclobutylmethoxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 120 methylN-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl- L-serinateExample 121 methylN-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-threoninate Example 1222-amino-N-((2S,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1232-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(propylamino)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1242-amino-N-((2S,3R)-3-(benzyloxy)-1-(cyclopentylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1252-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 126 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-alaninate Example 127benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-valinateExample 128 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-serinate Example 1293-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 1303-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 131(S)-3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide Example 1323-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 1333-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 1342-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example135 2-amino-N-((1S,2S)-2-((4′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example136 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(methylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 137 2-amino-N-((1S,2S)-2-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example138 2-amino-N-((1S,2S)-2-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example139 2-amino-N-((1S,2S)-2-((3′-amino-2′-methyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example140 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example141 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example142 2-amino-N-((1S,2S)-2-((4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example143 2-amino-N-((1S,2S)-2-((3′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example144 2-amino-N-((1S,2S)-2-((4′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example145 2-amino-N-((1S,2S)-2-((4′-(2-aminoethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example146 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamide Example 1472-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 1482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamideExample 1492-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(4-methyl-piperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 1512-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-((4-methyl-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 1522-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholine-4-carbonyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 153 2-amino-N-((1S,2S)-2-((4′-ethyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example154 2-amino-N-((1S,2S)-2-((4′-(cyanomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example155 2-amino-N-((1S,2S)-2-((4′-carbamoyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example156 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1572-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1582-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1592-amino-N-((1S,2S)-2-((2-chloro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1602-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example161 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1622-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 1632-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 1642-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1652-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1662-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamide Example 1672-amino-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1682-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamideExample 169 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example170 2-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example171 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example172 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1732-amino-N-((1S,2S)-2-((4′-(((2-hydroxyethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1742-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1752-amino-N-((1S,2S)-2-((4′-((3,3-difluoropiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1762-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1772-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example178 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-phenylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1792-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1802-amino-N-((1S,2S)-2-((4′-((4-hydroxypiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1812-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1822-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1832-amino-N-((1S,2S)-2-((4′-((4-ethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1842-amino-N-((1S,2S)-2-((4′-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1852-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((R)-3-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1862-amino-N-((1S,2S)-2-((4′-(((R)-3,4-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1872-amino-N-((1S,2S)-2-((4′-(((R)-2,4-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1882-amino-N-((1S,2S)-2-((4′-((3-ethyl-4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1892-amino-N-((1S,2S)-2-((4′-((cis-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1902-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1912-amino-N-((1S,2S)-2-((4′-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1922-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1932-amino-N-((1S,2S)-2-((4′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1943-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)pyrazine-2-carboxamide Example 1952-amino-N-((1S,2S)-2-((3′-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1962-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1972-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1982-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-methyl-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1992-amino-N-((1S,2S)-2-((3′-hydroxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2002-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-nitro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2012-amino-N-((1S,2S)-2-((3′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2022-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2032-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 2042-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 2052-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2062-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2072-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamideExample 2082-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2092-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2102-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2112-amino-N-((1S,2S)-2-((4′-(1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example212 2-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example213 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2142-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2152-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2162-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2172-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2182-amino-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2192-amino-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2202-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2212-amino-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2226-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2236-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2246-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2256-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2266-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2276-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2286-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2296-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2306-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2312-amino-5-chloro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2322-amino-5-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2332-amino-5-cyano-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2342-amino-6-chloro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2352-amino-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2366-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2376-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2386-amino-2′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methylpiperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2402-amino-N-((1S,2S)-2-((4′-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 241 methyl2-(4-((4′-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)-[1,1′-biphenyl]-4-yl)methyl)piperidin-1-yl)acetate Example 2422-amino-N-((1S,2S)-2-((4′-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2432-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide Example244 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2452-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 2462-amino-N-((1S,2S)-2-((4′-(3-(dimethylamino)propoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 247 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methylpiperidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2482-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)prop-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 249 2-amino-N-((1S,2S)-2-((4-(4-hydroxybut-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 250 2-amino-N-((1S,2S)-2-((4-(5-hydroxypent-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 251 2-amino-N-((1S,2S)-2-((4-(6-hydroxyhex-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 252 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(4-(4-methylpiperazin-1-yl)but-1-yn-1- yl)benzyl)oxy)cyclopentyl)nicotinamideExample 253 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 2542-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2552-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2572-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2582-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2592-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2602-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2612-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2622-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example263 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamideExample 264 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)nicotinamide Example 2652-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)nicotinamide Example 2662-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)phenyl)nicotinamide Example 2672-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)nicotinamide Example 2682-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 2696-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-bipyridine]-5-carboxamide Example 2702-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 2712-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 2722-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 2732-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 2742-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 2752-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example 2762-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 2772-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 2782-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide Example 2792-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamide Example 2802-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamideExample 2812-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example282 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamide Example 2832-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 2842-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 2852-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 2862-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 2872-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamide Example 2882-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide Example289 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 2902-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide Example 2912-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 2922-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 2932-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide Example 2946-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2′-methoxy-[3,3′-bipyridine]-5-carboxamide Example 2952-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 2962-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxyphenyl)nicotinamide Example 2972-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 2982-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methylsulfonamido)phenyl)nicotinamide Example 2992-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxymethyl)phenyl)nicotinamide Example 3002-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3012-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxypropyl)phenyl)nicotinamide Example 3022-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide Example3032-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 3042-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamide Example 3053-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acid Example 3064-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-2-methylbenzoic acid Example 3072-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)nicotinamide Example 308 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidExample 309 3-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidExample 3102-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideExample 3112-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 3122-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)-phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)- nicotinamideExample 3132-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 3142-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formylphenyl)nicotinamide Example 315 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidExample 316 3-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3- yl)phenyl)propanoicacid Example 3172-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxyphenyl)nicotinamide Example 3182-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 3192-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamide Example 3202-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 3216-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-bipyridine]-5-carboxamide Example 3222-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidExample 3232-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamide Example 3242-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamide Example 3252-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamideExample 3262-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamide Example 3272-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3282-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 3292-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamideExample 3302-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideExample 331 2-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3322-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3332-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamide Example 3342-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3352-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)nicotinamide Example 3362-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamide Example 3372-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3382-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3392-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3402-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3412-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3422-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3432-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3442-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3452-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide Example 3462-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example347 2-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example348 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3492-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3502-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 3512-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamide Example 3522-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamide Example 3532-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 354amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamide Example 3552-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3562-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 3572-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide Example358 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3592-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example 3602-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamideExample 3613-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 362(S)-3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide Example 3632-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3642-amino-5-(3,4-difluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 3652-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide Example 3662-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 3672-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide Example 3682-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 3692-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 3702-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide Example 3712-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide Example 3722-amino-5-(4-hydroxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example373 2-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 3742-amino-5-methyl-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 3756-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 3762-amino-5-(4-methoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example377 6-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamideExample 3782-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide Example 3792-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 3802-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 3812-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4- morpholinophenyl)nicotinamideExample 3822-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 383 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 3846-amino-2′,6′-difluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamide Example 3852-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide Example 3866-amino-6′-fluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 3872-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)nicotinamide Example 3882-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 3892-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 3902-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 3912-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 3922-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamide Example 3934-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoic acid Example 3942-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamide Example 3956-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4′-bipyridine]-5-carboxamide Example 3966-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3′-bipyridine]-5-carboxamide Example 3972-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamide Example 3982-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamide Example 3992-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamide Example 4002-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4012-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamide Example 4022-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamide Example 4035-([1,1′-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4042-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4052-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4062-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamide Example 4072-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4082-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamide Example 4092-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide Example 4102-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamide Example 4112-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4122-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 4132-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 4142-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4152-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4162-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4172-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4182-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4192-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 4202-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide Example 4212-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonyl)phenyl)nicotinamide Example 4222-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4232-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide Example 4242-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 4252-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4262-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example427 2-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4282-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamideExample 429 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 430 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 4312-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4322-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4332-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 4342-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4352-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4362-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamid Example 4372-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4382-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4402-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4412-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4422-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4432-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4442-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4452-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4462-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4472-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4492-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4512-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4522-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4532-amino-N-((3S,4R)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4542-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4552-amino-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamide Example 4572-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(phenylamino)nicotinamide Example 4582-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)nicotinamide

Pharmaceutical Compositions Comprising of Novel Mer Kinase Inhibitors

The present invention provides pharmaceutical compositions comprisingthe heterocyclic compounds, the stereoisomer thereof, the enantiomerthereof, or the pharmaceutically acceptable salt thereof together withpharmaceutically acceptable carriers.

The carriers that are used in the present invention may be those thatare conventionally used in the art, and examples thereof include, butare not limited to, sugar, starch, microcrystalline cellulose, lactose(lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metalsalts, clay, polyethylene glycol, anhydrous dibasic calcium phosphate,or mixtures thereof.

Further, according to another embodiment of the present invention, thepharmaceutical compositions may contain additives such as binders,disintegrants, lubricants, pH-adjusting agents, antioxidants, and thelike.

Examples of the binders that may be used in the present inventioninclude, but are not limited to, starch, microcrystalline cellulose,highly dispersed silica, mannitol, di-mannitol, sucrose, lactosehydrate, polyethylene glycol, polyvinylpyrrolidone (povidone),polyvinylpyrrolidone copolymer (copovidone), hypromellose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin, or mixturesthereof.

Examples of the disintegrants that may be used in the present inventioninclude, but are not limited to, starches or modified starches such assodium starch glyconate, maize starch, potato starch or pregelatinizedstarch; clays such as bentonite, montmorillonite, or veegum; cellulosessuch as microcrystalline cellulose, hydroxypropylcellulose orcarboxymethylcellulose; algins such as sodium alginate or alginic acid;crosslinked celluloses such as croscarmellose sodium; gums such as guargum or xanthan gum; crosslinked polymers such as crosslinkedpolyvinylpyrrolidone (crospovidone); effervescent formulations such assodium bicarbonate or citric acid; or mixtures thereof.

Examples of the lubricants that may be used in the present inventioninclude, but are not limited to, talc, stearic acid, magnesium stearate,calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil,sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glycerylmonooleate, glyceryl monostearate, glyceryl palmitostearate, colloidalsilicon dioxide, or mixtures thereof.

Examples of the pH-adjusting agents that may be used in the presentinvention include, but are not limited to, acidifying agents such asacetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodiumetherate, malic acid, succinic acid, tartaric acid, fumaric acid orcitric acid, and basifying agents such as precipitated calciumcarbonate, ammonia water, meglumine, sodium carbonate, magnesium oxide,magnesium carbonate, sodium citrate, or tribasic calcium phosphate.

Examples of the antioxidants that may be used in the present inventioninclude, but are not limited to, dibutyl hydroxytoluene, butylatedhydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodiumhydrogen sulfite, sodium pyrosulfite, and the like.

The present invention provides the pharmaceutical compositions comprise,as active ingredients, the heterocyclic compounds, the stereoisomerthereof, the enantiomer thereof, or the pharmaceutically acceptable saltthereof and are used for prevention or treatment of a disease which isinfluenced by inhibition of Mer kinase.

The present invention provides the disease which is influenced byinhibition of Mer kinase is cancer or immune-related diseases.

The cancer is selected from the group consisting of: glioma,gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, smallcell lung carcinoma, cervical carcinoma, colon cancer, rectal cancer,chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, colorectal cancer, endometrium cancer,ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renalcell carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma,seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladdercarcinoma, angiosarcoma, endotheliosarcoma, adenocarcinoma, sweat glandcarcinoma, sebaceous gland sarcoma, papillary sarcoma, papillaryadenosarcoma, cystadenosarcoma, bronchogenic carcinoma, medullarycarcinoma, mastocytoma, mesotheliorma, synovioma, melanoma,leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma,oligodentroglioma, acoustic neuroma, hemangioblastoma, meningioma,pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma,embryonal carcinoma, squamous cell carcinoma, base cell carcinoma,fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, leukemia and metastatic lesions secondary to theseprimary tumors.

The immune-related disease is selected from the group consisting ofinfection and sepsis.

The term “treatment” is used to refer to both prevention of diseases andtreatment of pre-existing conditions.

The therapeutic amount varies according to the specific disease and canbe determined by the person skilled in the art without undue effort.

In addition, the subject in the prevention or treatment method of thepresent invention includes mammals, particularly humans.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

Method for Prevention or Treatment of Immune-Related Diseases or Cancer

The present invention provides a method of treating or preventingimmune-related diseases or cancer, the method comprising administeringto a mammals including humans in need thereof compositions comprising,as active ingredients, the heterocyclic compounds, isomers thereof orpharmaceutically acceptable salts thereof.

The composition that is used in the inventive method for preventing ortreating immune-related diseases or cancer includes the pharmaceuticalcomposition described in the specification

The present invention provides use of compositions comprising, as activeingredients, the heterocyclic compounds, the stereoisomer thereof, theenantiomer thereof, or the pharmaceutically acceptable salt thereof forpreparation of medicaments for preventing or treating cancer orimmune-related diseases.

Methods for Preparing of Novel Mer Kinase Inhibitors

The compounds of this invention can be prepared in accordance with oneor more of schemes discussed below.

These methods can be used either directly or with obvious variations totrained chemists to prepare key intermediates and certain compounds ofthis invention.

Suitable synthetic sequences are readily selected per specificstructures of this invention, but within the art known to individualspracticing organic synthesis, such as methods summarized in availablechemistry data bases, as in CAS Scifinder and Elesevier Reaxys. Based onthese general methods, the enablement for making the compounds of thisinvention is straightforward and can be practiced within a commonprofessional knowledge. Some general synthetic methods to prepare thecompounds of this invention are illustrated below in Schemes 1-2(non-limiting, for illustration only).

One general approach to the compounds of this invention is illustratedin general

Scheme 1. General Procedure A

a) NBS, CH₃CN, H₂O; b) R¹—B(OH)₂ or its pinacol ester, Pd(PPh₃)₄, aq.K₃PO₄, Dioxane, heat; c) NaOH, MeOH, heat; d) HATU, TEA, DMF

Another general approach to the compounds of this invention isillustrated in general

Scheme 2. General Procedure B

a) NaOH, MeOH, heat; b) HATU, TEA, DMF; c) R¹—B(OH)₂ or its pinacolester, Pd(PPh₃)₄, aq. K₃PO₄, Dioxane, heat

Advantageous Effects

Novel heterocyclic compounds according to the present invention, astereoisomer thereof, an enantiomer thereof, or a pharmaceuticallyacceptable salt thereof exhibit the effect of effectively inhibiting Merkinase.

Novel heterocyclic compounds according to the present invention, astereoisomer thereof, an enantiomer thereof, or a pharmaceuticallyacceptable salt can be used for the prevention or treatment of cancer orimmune-related disease.

MODE FOR INVENTION

Based on the studies conducted and the results obtained so far, it isbelieved that the following compounds (numbered 1 to 458), includingisomers, mixtures of isomer as well as pharmaceutically acceptable saltsand solvates thereof, are particularly interesting.

General Synthetic Methods Examples

Embodiments of the present invention are described in the followingexamples, which are meant to illustrate and not limit the scope of thisinvention. Common abbreviations well known to those with ordinary skillsin the synthetic art used throughout.

All chemical reagents were commercially available. Flash columnchromatography means silica gel chromatography unless specifiedotherwise, which was performed on Teledyne Combiflash-RF200 System. ¹HNMR spectra (δ, ppm) are recorded on 400 MHz or 600 MHz instrument. Massspectroscopy data for a positive ionization method are provided.Preparative HPLC was performed on Agilent technologies G1361A.

Example 12-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 1:

Intermediate 1

To a mixture of methyl 2-amino-5-bromonicotinate (1.5 g, 6.5 mmol) and1-Methylpyrazole-4-boronic acid pinacol ester (1.76 g, 8.5 mmol) in 24ml of 1,4-dioxane was added 8 ml of aq. 2N K₃PO₄ followed by Pd(PPh₃)₄(370 mg, 0.32 mmol). The reaction mixture was heated at 100° C. for 3hrs, cooled to room temperature, and extracted with EtOAc, dried overanhydrous MgSO₄ and concentrated under vacuum. The crude product waspurified by silicagel column chromatography to give 1.25 g of off-whitesolid.

¹H NMR (400 MHz, CD₃OD) δ 3.90 (s, 3H), 3.91 (s, 3H), 7.74 (s, 1H), 7.91(s, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H);

MS (ESI, m/z): 233.1 [M+H]⁺

Intermediate 2

To a suspension of intermediate 1 (1.2 g, 5.17 mmol) in 26 ml of MeOHwas added 2N NaOH (4.3 ml, 8.63 mmol) and the mixture was heated at 65°C. for 1 hr, cooled to room temperature, neutralized (4.3 ml of 2N HCl),and the resulting precipitate was filtered, washed with MeOH, and driedto give 0.97 g of off-white solid.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 3.82 (s, 3H), 5.73 (s, 2H), 7.77 (s,1H), 8.05 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H); MS(ESI, m/z): 219.1 [M+H]⁺

Example 12-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 2 (43 mg, 0.2 mmol) and triethylamine (24mg, 0.24 mmol) in 2 ml of DMF was added HATU (91 mg, 0.24 mmol) followedby (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (38 mg, 0.2 mmol). Themixture was stirred at room temperature for 1 hr and then saturatedsodium bicarbonate solution was added. The mixture was extracted withEtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo.The crude residue was purified by preparative HPLC to afford 46 mg ofthe title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.57-1.69 (m, 1H) 1.72-1.86 (m, 3H)1.90-2.08 (m, 1H) 2.11-2.21 (m, 1H) 3.93 (s, 3H) 3.96 (dt, J=6.75, 4.26Hz, 1H) 4.39 (td, J=7.34, 4.11 Hz, 1H) 4.61 (s, 2H) 7.13-7.24 (m, 1H)7.27 (t, J=7.46 Hz, 2H) 7.32 (d, J=7.04 Hz, 2H) 7.79-7.90 (m, 1H) 8.00(s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.46 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 392.2 [M+H]⁺

Example 22-amino-N-(1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-(benzyloxy)cyclopentan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 392.2 [M+H]⁺

Example 32-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-(benzyloxy)cyclopentan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 392.2 [M+H]⁺

Example 42-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2S)-2-(benzyloxy)cyclopentan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 392.2 [M+H]⁺

Example 52-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using cis-2-(benzyloxy)cyclopentan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 392.2 [M+H]⁺

Example 62-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((2-methylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 406.2 [M+H]⁺

Example 72-amino-N-(1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 82-amino-N-(1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 92-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((4-ethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 102-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 112-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 122-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 132-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 142-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 152-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 162-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 172-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 182-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 192-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 202-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 448.3 [M+H]⁺

Example 212-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 222-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-propylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 232-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 460.3 [M+H]⁺

Example 242-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 252-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (1 S,2 S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentan-1-amine,the title compound was obtained as described for the example 1.

MS (ESI, m/z): 432.2 [M+H]⁺

Example 262-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 432.2 [M+H]⁺

Example 272-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 446.3 [M+H]⁺

Example 282-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 416.2 [M+H]⁺

Example 292-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 460.2 [M+H]⁺

Example 302-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2 S)-2-((3-nitrobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 437.2 [M+H]⁺

Example 312-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzonitrile, the titlecompound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.70 (m, 1H) 1.73-1.90 (m, 3H)1.95-2.07 (m, 1H) 2.11-2.22 (m, 1H) 3.88-3.98 (m, 4H) 4.36-4.44 (m, 1H)4.61-4.72 (m, 2H) 7.43-7.51 (m, 1H) 7.57 (br d, J=7.43 Hz, 1H) 7.63 (brd, J=7.43 Hz, 1H) 7.70 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.23 (d, J=1.96Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 417.2 [M+H]⁺

Example 322-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 408.2 [M+H]⁺

Example 332-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.54-1.65 (m, 1H) 1.68-1.88 (m, 3H)1.95-2.07 (m, 1H) 2.09-2.22 (m, 1H) 3.65-3.74 (m, 3H) 3.88-3.98 (m, 4H)4.33-4.43 (m, 1H) 4.51-4.66 (m, 2H) 6.74 (dd, J=8.41, 1.76 Hz, 1H)6.83-6.93 (m, 2H) 7.12-7.22 (m, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d,J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 422.2 [M+H]⁺

Example 342-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 422.2 [M+H]⁺

Example 352-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 422.2 [M+H]⁺

Example 362-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 422.2 [M+H]⁺

Example 372-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 452.2 [M+H]⁺

Example 382-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 452.2 [M+H]⁺

Example 392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 484.2 [M+H]⁺

Example 402-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-yl-methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentan-1-amine,the title compound was obtained as described for the example 1.

MS (ESI, m/z): 436.2 [M+H]⁺

Example 412-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 438.2 [M+H]⁺

Example 42 methyl3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate

Using methyl 3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzoate, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 450.2 [M+H]⁺

Example 432-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.50, 6.46 Hz, 1H)1.72-1.87 (m, 3H) 1.94-2.05 (m, 1H) 2.16 (br d, J=6.65 Hz, 1H) 3.89-3.97(m, 4H) 4.38 (br d, J=4.70 Hz, 1H) 4.55-4.66 (m, 2H) 7.20 (br s, 1H)7.22-7.28 (m, 2H) 7.34 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=2.35Hz, 1H) 8.44 (br d, J=2.35 Hz, 1H); MS (ESI, m/z): 426.2 [M+H]⁺

Example 442-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3-chlorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 426.2 [M+H]⁺

Example 452-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((4-chlorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 426.2 [M+H]⁺

Example 462-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3,4-dichlorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 460.1 [M+H]⁺

Example 472-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((2-fluorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 410.2 [M+H]⁺

Example 482-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (dq, J=13.69, 7.17 Hz, 1H) 1.70-1.88(m, 3H) 1.93-2.06 (m, 1H) 2.15 (dt, J=13.69, 6.85 Hz, 1H) 3.87-4.00 (m,4H) 4.34-4.42 (m, 1H) 4.62 (s, 2H) 6.92 (td, J=8.61, 1.96 Hz, 1H)7.03-7.16 (m, 2H) 7.27 (dd, J=8.02, 6.06 Hz, 1H) 7.85 (s, 1H) 8.00 (s,1H) 8.22 (d, J=1.96 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H); MS (ESI, m/z):410.2 [M+H]⁺

Example 492-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 488.1/490.1 [M+H]⁺

Example 502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamide

Using trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 446.2 [M+H]⁺

Example 512-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-bromobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 470.1/472.1 [M+H]⁺

Example 522-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 488.1/490.1 [M+H]⁺

Example 532-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 488.1/490.1 [M+H]⁺

Example 542-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 484.1/486.1 [M+H]⁺

Example 55 methyl(3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoyl)glycinate

Using methyl(3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzoyl)glycinate, the titlecompound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.70 (m, 1H) 1.73-1.90 (m, 3H)1.95-2.07 (m, 1H) 2.11-2.22 (m, 1H) 3.88-3.98 (m, 4H) 4.36-4.44 (m, 1H)4.61-4.72 (m, 2H) 7.43-7.51 (m, 1H) 7.57 (br d, J=7.43 Hz, 1H) 7.63 (brd, J=7.43 Hz, 1H) 7.70 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.23 (d, J=1.96Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 507.2[M+H]⁺

Example 562-amino-N-((1S,2S)-2-((3-((2-hydroxyethyl)carbamoyl)benzyl)-oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using methyl(3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)-N-(2-hydroxyethyl)-benzamide,the title compound was obtained as described for the example 1.

MS (ESI, m/z): 479.2[M+H]⁺

Example 572-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)oxy)cyclopentyl)nicotinamide

Using tert-butyl4-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)carbamoyl)-piperidine-1-carboxylate,the title compound was obtained as described for the example 1 andfollowing deprotection with TFA.

MS (ESI, m/z): 518.3[M+H]⁺

Example 582-amino-N-((1S,2S)-2-((3-((S)-2-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl((S)-1-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)carbamate,the title compound was obtained as described for the example 1 andfollowing deprotection with TFA.

MS (ESI, m/z): 478.3[M+H]⁺

Example 59N-((1S,2S)-2-((3-((S)-2-acetamidopropanamido)benzyl)oxy)-cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(S)-2-acetamido-N-(3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)-propanamide,the title compound was obtained as described for the example 1.

MS (ESI, m/z): 520.3[M+H]⁺

Example 602-amino-N-((1S,2S)-2-((3-(3-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl(3-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)amino)-3-oxopropyl)carbamate,the title compound was obtained as described for the example 1 andfollowing deprotection with TFA.

MS (ESI, m/z): 478.3[M+H]⁺

Example 61N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 459.2 [M+H]⁺

Example 62N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 459.2 [M+H]⁺

Example 632-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 442.2 [M+H]⁺

Example 642-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 443.2 [M+H]⁺

Example 652-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using(1S,2S)-2-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentan-1-amine,the title compound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br d, J=5.87 Hz, 2H) 1.67-1.87 (m,5H) 1.93-2.09 (m, 2H) 2.14 (br s, 3H) 2.28 (br s, 2H) 3.92 (s, 3H) 4.37(br d, J=5.48 Hz, 1H) 4.49-4.65 (m, 2H) 6.00 (br s, 1H) 7.18-7.30 (m,2H) 7.54 (br s, 1H) 7.59-7.69 (m, 1H) 7.84 (s, 1H) 7.98 (s, 1H) 8.23 (s,1H) 8.38 (s, 1H);

MS (ESI, m/z): 472.3 [M+H]⁺

Example 66N-(trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 468.2 [M+H]⁺

Example 67N-((1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 468.2 [M+H]⁺

Example 68N-((1S,2S)-2-([1,1′-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-3-([1,1′-biphenyl]-4-ylmethoxy)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.59 (br d, J=1.17 Hz, 1H) 1.79 (br s, 3H)1.97 (br s, 1H) 2.11-2.21 (m, 1H) 3.62 (s, 2H) 3.87 (s, 3H) 3.97 (br s,1H) 4.39 (br s, 1H) 4.65 (br d, J=13.69 Hz, 2H) 7.34-7.42 (m, 2H) 7.50(br t, J=7.43 Hz, 2H) 7.80 (s, 1H) 7.90 (s, 1H) 8.17 (br s, 1H)8.29-8.34 (m, 1H); MS (ESI, m/z): 468.2 [M+H]⁺

Example 692-amino-N-((1S,2S)-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-aminocyclopentan-1-ol, the title compound was obtainedas described for the example 1.

MS (ESI, m/z): 302.2 [M+H]⁺

Example 702-amino-N-(cis-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using cis-2-aminocyclopentan-1-ol, the title compound was obtained asdescribed for the example 1.

MS (ESI, m/z): 302.2 [M+H]⁺

Example 71N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 72N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-((3,4-dimethylbenzyl-)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using2-((3,4-dimethylbenzyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinicacid, the title compound was obtained as described for the example 1.

MS (ESI, m/z): 510.3 [M+H]⁺

Example 732-amino-N-((6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 450.2 [M+H]⁺

Example 742-amino-N-(trans-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-(benzyloxy)cyclohexan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 406.2 [M+H]⁺

Example 752-amino-N-((1S,2S)-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(benzyloxy)cyclohexan-1-amine, the title compound wasobtained as described for the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.28-1.47 (m, 4H) 1.77 (br s, 1H) 1.83 (brs, 1H) 1.97 (s, 1H) 2.29 (br s, 1H) 3.38 (br d, J=9.39 Hz, 1H) 3.92 (s,3H) 3.99 (br d, J=10.17 Hz, 1H) 4.41-4.47 (m, 1H) 4.68 (br d, J=12.13Hz, 1H) 7.13 (dt, J=14.57, 6.99 Hz, 3H) 7.25 (br d, J=7.43 Hz, 2H) 7.77(s, 1H) 7.89 (s, 1H) 8.21 (s, 1H) 8.25 (br s, 1H); MS (ESI, m/z): 406.2[M+H]⁺

Example 762-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-N1-benzyl-N1-methylcyclopentane-1,2-diamine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 405.2 [M+H]⁺

Example 772-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-(phenoxymethyl)cyclopentan-1-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 392.2 [M+H]⁺

Example 782-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 792-amino-N-(trans-2,2-difluoro-5-(phenoxymethyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (trans-2,2-difluoro-5-(phenoxymethyl)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 428.2 [M+H]⁺

Example 802-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)-methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentan-1-amine,the title compound was obtained as described for the example 1.

MS (ESI, m/z): 432.2 [M+H]⁺

Example 812-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentan-1-amine, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 822-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)-methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-(((1S,2S)-2-aminocyclopentyl)methoxy)-N,N-dimethylaniline, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 435.2 [M+H]⁺

Example 832-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide

Using(3-(((1S,2S)-2-aminocyclopentyl)methoxy)phenyl)(piperidin-1-yl)methanone,the title compound was obtained as described for the example 1.

MS (ESI, m/z): 503.3 [M+H]⁺

Example 842-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 484.2 [M+H]⁺

Example 852-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((benzyloxy)methyl)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 406.2 [M+H]⁺

Example 862-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentyl)nicotinamide

Using(1S,2S)-2-(((4′-(4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentan-1-amine,the title compound was obtained as described for the example 1.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.56-1.65 (m, 1H) 1.67-1.75 (m, 1H) 1.79(br d, J=6.46 Hz, 1H) 1.85 (br d, J=8.80 Hz, 1H) 2.03-2.12 (m, 1H) 2.16(br dd, J=12.91, 5.87 Hz, 1H) 2.43-2.51 (m, 1H) 2.84 (s, 3H) 3.75 (s,2H) 3.89 (s, 3H) 4.10 (d, J=5.87 Hz, 2H) 4.30-4.38 (m, 1H) 6.96 (d,J=8.80 Hz, 2H) 7.38 (br d, J=8.22 Hz, 2H) 7.50 (dd, J=16.43, 8.22 Hz,4H) 7.86 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35Hz, 1H);

MS (ESI, m/z): 580.3 [M+H]⁺

Example 87 (1S,2S)-2-(benzyloxy)cyclopentyl2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinate

Using (1S,2S)-2-(benzyloxy)cyclopentan-1-ol, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 393.2 [M+H]⁺

Example 882-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamide

Using (1S,2R)-2-phenethylcyclopentan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 390.2 [M+H]⁺

Example 892-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 394.2 [M+H]⁺

Example 902-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-morpholinotetrahydrofuran-3-yl)nicotinamide

Using trans-4-morpholinotetrahydrofuran-3-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 373.2 [M+H]⁺

Example 912-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)nicotinamide

Using trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 357.2 [M+H]⁺

Example 922-amino-N-(cis-4-hydroxytetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using cis-4-aminotetrahydrofuran-3-ol, the title compound was obtainedas described for the example 1.

MS (ESI, m/z): 304.1 [M+H]⁺

Example 932-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-4-(benzyloxy)-1-methylpyrrolidin-3-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 407.2 [M+H]⁺

Example 942-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 435.2 [M+H]⁺

Example 95(R)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-(benzyloxy)propan-1-amine, the title compound was obtainedas described for the example 1.

MS (ESI, m/z): 366.2 [M+H]⁺

Example 96(S)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-(benzyloxy)propan-1-amine, the title compound was obtainedas described for the example 1.

MS (ESI, m/z): 366.2 [M+H]⁺

Example 97(S)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)propan-2-amine, the title compound was obtainedas described for the example 1.

MS (ESI, m/z): 366.2 [M+H]⁺

Example 98(R)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)propan-2-amine, the title compound was obtainedas described for the example 1.

MS (ESI, m/z): 366.2 [M+H]⁺

Example 992-amino-N-(1-(benzyloxy)-2-methylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-(benzyloxy)-2-methylpropan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 380.2 [M+H]⁺

Example 100(R)-2-amino-N-(1-((3,4-dimethylbenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((3,4-dimethylbenzyl)oxy)propan-2-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 394.2 [M+H]⁺

Example 101(S)-2-amino-N-(2-((3,4-dimethylbenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((3,4-dimethylbenzyl)oxy)propan-1-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 394.2 [M+H]⁺

Example 102(R)-2-amino-N-(1-((4-chlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((4-chlorobenzyl)oxy)propan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 400.2 [M+H]⁺

Example 103(S)-2-amino-N-(2-((4-chlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((4-chlorobenzyl)oxy)propan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 400.2 [M+H]⁺

Example 104(R)-2-amino-N-(1-((3,4-dichlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((3,4-dichlorolbenzyl)oxy)propan-2-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 434.1 [M+H]⁺

Example 105(S)-2-amino-N-(2-((3,4-dichlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((3,4-dichlorobenzyl)oxy)propan-1-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 419.1 [M+H]⁺

Example 106(R)-2-amino-N-(1-((3-methoxybenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((3-methoxybenzyl)oxy)propan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 396.2 [M+H]⁺

Example 107(S)-2-amino-N-(2-((3-methoxybenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((3-methoxybenzyl)oxy)propan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 396.2 [M+H]⁺

Example 108(R)-2-amino-N-(1-(benzyloxy)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)butan-2-amine, the title compound was obtained asdescribed for the example 1.

MS (ESI, m/z): 380.2 [M+H]⁺

Example 109(S)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)-3-methylbutan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 394.2 [M+H]⁺

Example 110(R)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)-3-methylbutan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 394.2 [M+H]⁺

Example 111(S)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)-4-methylpentan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 408.2 [M+H]⁺

Example 112(R)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)-4-methylpentan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 408.2 [M+H]⁺

Example 113(R)-2-amino-N-(2-(benzyloxy)-1-cyclohexylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-(benzyloxy)-1-cyclohexylethan-1-amine, the title compoundwas obtained as described for the example 1.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 114(R)-2-amino-N-(1-cyclohexyl-2-hydroxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-amino-2-cyclohexylethan-1-ol, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 344.3 [M+H]⁺

Example 115(S)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-(benzyloxy)-1-phenylethan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 428.2 [M+H]⁺

Example 116(R)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-(benzyloxy)-1-phenylethan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 428.2 [M+H]⁺

Example 117(S)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)-3-phenylpropan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 442.2 [M+H]⁺

Example 118(R)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)-3-phenylpropan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 442.2 [M+H]⁺

Example 119(R)-2-amino-N-(1-(cyclobutylmethoxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(cyclobutylmethoxy)propan-2-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 344.2 [M+H]⁺

Example 120 methylN-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-serinate

Using methyl O-benzyl-L-serinate, the title compound was obtained asdescribed for the example 1.

MS (ESI, m/z): 410.2 [M+H]⁺

Example 121 methylN-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-threoninate

Using methyl O-benzyl-L-threoninate, the title compound was obtained asdescribed for the example 1.

MS (ESI, m/z): 424.2 [M+H]⁺

Example 1222-amino-N-((2S,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 423.2 [M+H]⁺

Example 1232-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(propylamino)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-N-propylbutanamide, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 451.2 [M+H]⁺

Example 1242-amino-N-((2S,3R)-3-(benzyloxy)-1-(cyclopentylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-N-cyclopentylbutanamide, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 477.3 [M+H]⁺

Example 1252-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-1-(pyrrolidin-1-yl)butan-1-one, thetitle compound was obtained as described for the example 1.

MS (ESI, m/z): 463.2 [M+H]⁺

Example 126 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-alaninate

Using benzyl L-alaninate, the title compound was obtained as describedfor the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.51 (d, J=7.43 Hz, 3H) 3.92 (s, 3H) 4.64(d, J=7.43 Hz, 1H) 5.12-5.25 (m, 2H) 7.21-7.42 (m, 5H) 7.84 (s, 1H)7.96-8.00 (m, 1H) 8.21-8.27 (m, 1H) 8.54 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 380.2 [M+H]⁺

Example 127 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-valinate

Using benzyl L-valinate, the title compound was obtained as describedfor the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.00 (dd, J=9.19, 6.85 Hz, 6H) 2.16-2.36(m, 1H) 4.46-4.55 (m, 1H) 5.10-5.30 (m, 2H) 7.22-7.41 (m, 5H) 7.84 (d,J=0.78 Hz, 1H) 7.98 (s, 1H) 8.24 (d, J=1.96 Hz, 1H) 8.48 (d, J=2.35 Hz,1H); MS (ESI, m/z): 408.2 [M+H]⁺

Example 128 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-serinate

Using benzyl L-serinate, the title compound was obtained as describedfor the example 1.

¹H NMR (400 MHz, CD₃OD) δ ppm 3.94-4.07 (m, 2H) 4.78 (dd, J=5.48, 4.30Hz, 1H) 5.21 (s, 2H) 7.23-7.43 (m, 5H) 7.86 (d, J=0.78 Hz, 1H) 8.01 (s,1H) 8.24 (d, J=1.96 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H); MS (ESI, m/z):396.2 [M+H]⁺

Example 1293-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and(1S,2S)-2-(benzyloxy)cyclopentan-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 393.2 [M+H]⁺

Example 1303-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the example 1.

MS (ESI, m/z): 421.2 [M+H]⁺

Example 131(S)-3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and(S)-1,2,3,4-tetrahydronaphthalen-1-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 349.2 [M+H]⁺

Example 1323-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid andtrans-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 395.2 [M+H]⁺

Example 1333-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid andcis-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound wasobtained as described for the example 1.

MS (ESI, m/z): 395.2 [M+H]⁺

Example 1342-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 134:

Intermediate 3

To a solution of methyl 2-amino-5-bromonicotinate (560 mg, 2.42 mmol) in10 ml of MeOH was added 2N NaOH (2 ml, 4 mmol) and the mixture washeated at 65° C. for 1 hr, cooled to room temperature, neutralized (2 mlof 2N HCl), and the resulting precipitate was filtered, washed withMeOH, and dried to give 0.35 g of white solid.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.17 (d, J=2.4 Hz, 1H), 8.23 (d, J=2.4 Hz,1H); MS (ESI, m/z): 217.0 [M+H]⁺

Intermediate 2

To a mixture of intermediate 3 (4.48 g, 20.6 mmol) and1-methylpyrazole-4-boronic acid pinacol ester (5.5 g, 26.8 mmol) in 100ml of 1,4-dioxane/water (3/1) was added K₂CO₃ (8.5 g, 61.9 mmol)followed by Pd(PPh₃)₄ (1.19 g, 1.03 mmol). The reaction mixture washeated at 100° C. for 3 hrs, cooled to room temperature, and partitionedbetween water and EtOAc. Water layer was separated and adjusted to pHvalue between 4 and 5. The precipitate was collected by filtration anddried to afford 4 g of the title compound. The crude product was usedfor the next step without further purification.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 3.82 (s, 3H), 5.73 (s, 2H), 7.77 (s,1H), 8.05 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H); MS(ESI, m/z): 219.1 [M+H]⁺

Intermediate 4

To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine(0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol)followed by (1S,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine (475 mg,1.76 mmol). The mixture was stirred at room temperature for 1 hr andthen saturated sodium bicarbonate solution was added. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified through silicagelcolumn chromatography to give 650 mg of off-white solid.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.59-1.69 (m, 1H) 1.72-1.78 (m, 1H)1.78-1.86 (m, 2H) 1.96-2.07 (m, 1H) 2.16 (dq, J=13.50, 6.85 Hz, 1H) 3.94(s, 3H) 3.95 (br d, J=1.76 Hz, 1H) 4.33-4.42 (m, 1H) 4.53-4.62 (m, 2H)7.25 (m, J=8.22 Hz, 2H) 7.41 (m, J=8.22 Hz, 2H) 7.87 (s, 1H) 8.01 (s,1H) 8.22 (d, J=1.76 Hz, 1H) 8.52 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 470.1/472.1 [M+H]⁺

Example 1342-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 4 (33 mg, 0.07 mmol) and(3-aminophenyl)boronic acid (11 mg, 0.08 mmol) in 0.4 ml of1,4-dioxane/water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed byPd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C.for 3 hrs, cooled to room temperature, and extracted with EtOAc, driedover anhydrous MgSO₄ and concentrated under vacuum. After concentrationunder vacuum, the crude residue was purified by preparative HPLC toafford 30 mg of the title compound.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.60-1.69 (m, 1H) 1.73-1.90 (m, 3H) 2.05(br d, J=7.04 Hz, 1H) 2.17 (s, 1H) 3.89 (s, 3H) 4.00 (br d, J=4.30 Hz,1H) 4.36-4.46 (m, 2H) 4.67 (s, 2H) 7.24 (br d, J=7.43 Hz, 1H) 7.42-7.59(m, 7H) 7.84 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.48 (d,J=2.35 Hz, 1H); MS (ESI, m/z): 483.2 [M+H]⁺

Example 1352-amino-N-((1S,2S)-2-((4′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-aminophenyl)boronic acid, the title compound was obtained asdescribed for the example 134.

MS (ESI, m/z): 483.2 [M+H]⁺

Example 1362-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(methylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-(methylamino)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br d, J=5.87 Hz, 1H) 1.73-1.94 (m,3H) 2.05 (br s, 1H) 2.17 (br s, 1H) 3.55 (br t, J=11.15 Hz, 3H) 3.90 (s,3H) 4.00 (br s, 1H) 4.43 (s, 4H) 4.67 (s, 2H) 7.45 (br d, J=8.22 Hz, 2H)7.55 (br d, J=7.83 Hz, 2H) 7.60 (br d, J=7.83 Hz, 2H) 7.71 (br d, J=7.83Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.21 (s, 1H) 8.52 (s, 1H);

MS (ESI, m/z): 497.3 [M+H]⁺

Example 1372-amino-N-((1S,2S)-2-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(dimethylamino)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

MS (ESI, m/z): 511.3 [M+H]⁺

Example 1382-amino-N-((1S,2S)-2-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using ((4-((dimethylamino)methyl)phenyl)boronic acid, the title compoundwas obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.55-1.68 (m, 1H) 1.80 (br s, 3H) 2.04 (brd, J=7.43 Hz, 1H) 2.15 (br s, 1H) 3.49 (br s, 3H) 3.62 (br s, 3H) 3.75(br s, 2H) 3.89 (s, 3H) 3.97 (br s, 1H) 4.39 (br s, 1H) 4.62 (br d,J=12.91 Hz, 1H) 4.66-4.73 (m, 1H) 7.44 (br t, J=9.19 Hz, 4H) 7.56 (br d,J=8.22 Hz, 2H) 7.62 (br d, J=7.83 Hz, 2H) 7.82 (s, 1H) 7.94 (s, 1H) 8.16(s, 1H) 8.42 (s, 1H); MS (ESI, m/z): 525.3 [M+H]⁺

Example 1392-amino-N-((1S,2S)-2-((3′-amino-2′-methyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-amino-2-methylphenyl)boronic acid, the title compound wasobtained as described for the example 134.

MS (ESI, m/z): 497.2 [M+H]⁺

Example 1402-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-hydroxyphenyl)boronic acid, the title compound was obtained asdescribed for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.61 (br d, J=7.43 Hz, 1H) 1.72-1.86 (m,3H) 1.95-2.08 (m, 1H) 2.09-2.20 (m, 1H) 3.87 (s, 3H) 3.97 (br s, 1H)4.40 (br d, J=18.00 Hz, 1H) 4.56-4.71 (m, 2H) 6.70-6.75 (m, 1H) 6.90 (brs, 1H) 6.95 (br d, J=7.83 Hz, 1H) 7.14-7.21 (m, 1H) 7.32-7.41 (m, 2H)7.42-7.50 (m, 2H) 7.78-7.83 (m, 1H) 7.88-7.93 (m, 1H) 8.16 (br d, J=1.96Hz, 1H) 8.36 (br d, J=2.35 Hz, 1H); MS (ESI, m/z): 484.2 [M+H]⁺

Example 1412-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(hydroxymethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

MS (ESI, m/z): 498.2 [M+H]⁺

Example 1422-amino-N-((1S,2S)-2-((4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using ((4-(hydroxymethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

MS (ESI, m/z): 498.2 [M+H]⁺

Example 1432-amino-N-(1S,2S)-2-((3′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(aminomethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.54-1.67 (m, 1H) 1.71-1.90 (m, 3H) 2.03(br dd, J=12.33, 7.04 Hz, 1H) 2.11-2.21 (m, 1H) 3.88 (s, 3H) 3.96-4.03(m, 1H) 4.16 (s, 2H) 4.35-4.47 (m, 1H) 4.67 (s, 2H) 7.40 (br d, J=7.63Hz, 1H) 7.44 (d, J=8.22 Hz, 1H) 7.49 (br t, J=7.63 Hz, 2H) 7.58 (d,J=7.63 Hz, 1H) 7.59-7.62 (m, 2H) 7.61 (br d, J=7.63 Hz, 1H) 7.66 (s, 1H)7.80 (s, 1H) 7.92 (s, 1H) 8.21 (d, J=2.35 Hz, 1H) 8.29 (br s, 1H); MS(ESI, m/z): 497.3 [M+H]⁺

Example 1442-amino-N-(1S,2S)-2-((4′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(aminomethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=14.09, 7.04 Hz, 1H)1.72-1.90 (m, 3H) 2.03 (br dd, J=13.21, 6.16 Hz, 1H) 2.14-2.23 (m, 1H)3.90 (s, 3H) 4.01 (br d, J=7.04 Hz, 1H) 4.14 (s, 2H) 4.40-4.45 (m, 1H)4.63-4.70 (m, 2H) 7.43 (d, J=8.22 Hz, 2H) 7.49 (d, J=7.63 Hz, 2H) 7.57(d, J=7.63 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.97 (s, 1H)8.21 (d, J=1.76 Hz, 1H) 8.49 (br s, 1H); MS (ESI, m/z): 497.3 [M+H]⁺

Example 1452-amino-N-((1S,2S)-2-((4′-(2-aminoethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(2-aminoethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

MS (ESI, m/z): 511.3 [M+H]⁺

Example 1462-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-(4-methylpiperazin-1-yl)phenyl)boronic acid, the title compoundwas obtained as described for the example 134.

MS (ESI, m/z): 566.3 [M+H]⁺

Example 1472-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (6-(piperazin-1-yl)pyridin-3-yl)boronic acid, the title compoundwas obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br d, J=7.83 Hz, 1H) 1.81 (br d,J=7.83 Hz, 3H) 2.04 (br s, 1H) 2.18 (br s, 1H) 3.32-3.40 (m, 4H) 3.84(br s, 4H) 3.90 (s, 3H) 3.98 (br s, 1H) 4.40 (br s, 1H) 4.65 (s, 2H)6.98-7.02 (m, 1H) 7.41 (br d, J=7.04 Hz, 2H) 7.50 (br d, J=7.83 Hz, 2H)7.83-7.89 (m, 2H) 7.96 (s, 1H) 8.20 (s, 1H) 8.35 (s, 1H) 8.48 (s, 1H);

MS (ESI, m/z): 553.3 [M+H]⁺

Example 1482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid, the titlecompound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.58-1.66 (m, 1H) 1.73-1.87 (m, 3H) 2.04(dq, J=13.72, 6.77 Hz, 1H) 2.16 (dt, J=13.35, 6.53 Hz, 1H) 2.96 (s, 3H)3.90 (s, 3H) 3.96-4.01 (m, 1H) 4.37-4.45 (m, 1H) 4.60-4.69 (m, 2H) 6.99(d, J=8.80 Hz, 1H) 7.41 (d, J=8.22 Hz, 2H) 7.50 (d, J=8.22 Hz, 2H) 7.83(s, 1H) 7.85 (d, J=2.35 Hz, 1H) 7.96 (s, 1H) 8.20 (d, J=2.35 Hz, 1H)8.36 (d, J=2.35 Hz, 1H) 8.45 (s, 1H); MS (ESI, m/z): 567.3 [M+H]⁺

Example 1492-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (3-(piperazin-1-yl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br d, J=5.87 Hz, 2H) 1.81 (br d,J=6.65 Hz, 3H) 1.96-2.07 (m, 1H) 2.17 (br s, 1H) 3.40 (br dd, J=19.95,5.87 Hz, 8H) 3.88 (s, 3H) 4.00 (br s, 1H) 4.40 (br s, 1H) 4.65 (s, 2H)6.99 (br d, J=7.43 Hz, 1H) 7.10 (br d, J=6.65 Hz, 1H) 7.16 (s, 1H) 7.32(t, J=7.60 Hz, 1H) 7.40 (d, J=7.83 Hz, 2H) 7.53 (d, J=8.61 Hz, 2H) 7.84(s, 1H) 7.95 (s, 1H) 8.19 (s, 1H) 8.46 (s, 1H);

MS (ESI, m/z): 552.3 [M+H]⁺

Example 1502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (3-(4-methylpiperazin-1-yl)phenyl)boronic acid, the title compoundwas obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.66 (s, 1H) 1.73-1.88 (m, 3H) 1.99-2.08(m, 1H) 2.17 (br dd, J=13.50, 5.87 Hz, 1H) 2.97 (s, 3H) 3.06 (br s, 2H)3.60 (br s, 2H) 3.88 (s, 3H) 3.96-4.03 (m, 1H) 4.41 (br d, J=4.70 Hz,1H) 4.61-4.70 (m, 2H) 6.99 (br d, J=8.80 Hz, 1H) 7.10 (br d, J=7.63 Hz,1H) 7.16 (s, 1H) 7.32 (t, J=7.92 Hz, 1H) 7.41 (d, J=8.22 Hz, 2H) 7.53(d, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.93 (s, 1H) 8.19 (d, J=1.76 Hz, 1H)8.35-8.41 (m, 1H); MS (ESI, m/z): 566.3 [M+H]⁺

Example 1512-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (3-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacolester, the title compound was obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (br dd, J=13.30, 6.26 Hz, 1H)1.76-1.90 (m, 3H) 1.99-2.10 (m, 1H) 2.18 (br dd, J=14.09, 6.65 Hz, 1H)2.85 (s, 3H) 3.78 (s, 2H) 3.91 (s, 3H) 4.02 (br s, 1H) 4.43 (br dd,J=10.96, 7.83 Hz, 1H) 4.68 (s, 2H) 7.34 (br d, J=7.43 Hz, 1H) 7.38-7.45(m, 3H) 7.51 (br d, J=7.83 Hz, 1H) 7.54-7.60 (m, 3H) 7.86 (s, 1H) 7.99(s, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H); MS (ESI, m/z):579.3 [M+H]⁺

Example 1522-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholine-4-carbonyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-(morpholine-4-carbonyl)phenyl)boronic acid, the title compoundwas obtained as described for the example 134.

MS (ESI, m/z): 581.3 [M+H]⁺

Example 1532-amino-N-((1S,2S)-2-((4′-ethyl-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-ethylphenyl)boronic acid, the title compound was obtained asdescribed for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.24 (t, J=7.63 Hz, 3H) 1.55-1.67 (m, 1H)1.73-1.86 (m, 3H) 2.01-2.08 (m, 1H) 2.16 (br dd, J=13.21, 5.58 Hz, 1H)2.66 (q, J=7.63 Hz, 2H) 3.87 (s, 3H) 3.93-3.99 (m, 1H) 4.38-4.42 (m, 1H)4.61 (d, J=12.91 Hz, 1H) 4.65-4.71 (m, 1H) 7.21 (d, J=7.63 Hz, 2H) 7.38(d, J=8.22 Hz, 2H) 7.41 (d, J=8.22 Hz, 2H) 7.50 (d, J=8.22 Hz, 2H) 7.82(s, 1H) 7.91 (s, 1H) 8.16 (d, J=1.76 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H); MS(ESI, m/z): 496.3 [M+H]⁺

Example 1542-amino-N-((1S,2S)-2-((4′-(cyanomethyl)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(cyanomethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 134.

MS (ESI, m/z): 507.2 [M+H]⁺

Example 1552-amino-N-((1S,2S)-2-((4′-carbamoyl-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-carbamoylphenyl)boronic acid, the title compound was obtainedas described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (s, 1H) 1.70-1.88 (m, 3H) 2.05 (s,1H) 2.16 (td, J=13.06, 7.92 Hz, 1H) 3.88 (s, 3H) 3.98 (br d, J=6.46 Hz,1H) 4.40 (br d, J=4.70 Hz, 1H) 4.63 (d, J=12.33 Hz, 1H) 4.70 (d, J=12.91Hz, 1H) 7.44 (d, J=8.22 Hz, 2H) 7.58 (d, J=8.22 Hz, 2H) 7.61 (d, J=8.80Hz, 2H) 7.81 (s, 1H) 7.89 (d, J=8.22 Hz, 2H) 7.92 (s, 1H) 8.17 (d,J=2.35 Hz, 1H) 8.38 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 511.2 [M+H]⁺

Example 1562-amino-N-((1S,2S)-2-((3-fluoro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the titlecompound was obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.30, 7.04 Hz, 1H)1.74-1.92 (m, 3H) 2.04 (br dd, J=12.72, 6.06 Hz, 1H) 2.17 (br dd,J=13.50, 6.46 Hz, 1H) 2.91 (s, 3H) 3.25 (br s, 4H) 3.47 (br s, 4H) 3.90(s, 3H) 3.96-4.08 (m, 1H) 4.12 (s, 2H) 4.34-4.45 (m, 1H) 4.64-4.78 (m,2H) 5.47 (s, 1H) 7.32 (br d, J=11.35 Hz, 1H) 7.40 (br d, J=7.83 Hz, 1H)7.47-7.57 (m, 3H) 7.62 (br d, J=7.83 Hz, 2H) 7.85 (s, 1H) 7.99 (s, 1H)8.18 (s, 1H) 8.55 (s, 1H); MS (ESI, m/z): 598.4 [M+H]⁺

Example 1572-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and(4-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)boronic acidpinacol ester, the title compound was obtained as described for theexample 134.

MS (ESI, m/z): 626.4 [M+H]⁺

Example 1582-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)nicotinamide

Using(1S,2S)-2-((4-bromo-2-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amineand 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, thetitle compound was obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.69 (dt, J=13.89, 6.75 Hz, 1H) 1.77-1.93(m, 3H) 2.01-2.12 (m, 1H) 2.13-2.30 (m, 1H) 2.87 (s, 3H) 3.75 (s, 2H)3.92 (s, 3H) 4.00-4.08 (m, 1H) 4.45 (br dd, J=11.54, 7.24 Hz, 1H) 7.47(d, J=8.22 Hz, 2H) 7.62 (m, J=8.22 Hz, 2H) 7.81-7.84 (m, 2H) 7.86 (d,J=5.09 Hz, 2H) 8.00 (s, 1H) 8.23 (d, J=1.96 Hz, 1H) 8.56 (d, J=2.35 Hz,1H);

MS (ESI, m/z): 648.3[M+H]⁺

Example 1592-amino-N-((1S,2S)-2-((2-chloro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (1S,2S)-2-((4-bromo-3-chlorobenzyl)oxy)cyclopentan-1-amine and4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the titlecompound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.65 (br dd, J=13.50, 7.04 Hz, 1H)1.74-1.89 (m, 3H) 1.97-2.11 (m, 1H) 2.15-2.22 (m, 1H) 2.85 (s, 3H) 3.72(s, 2H) 3.92 (s, 3H) 3.98 (dt, J=6.46, 4.11 Hz, 1H) 4.42 (td, J=7.34,4.11 Hz, 1H) 4.66 (d, J=2.35 Hz, 2H) 7.27 (d, J=7.63 Hz, 1H) 7.30-7.37(m, 3H) 7.40 (d, J=8.22 Hz, 2H) 7.47 (d, J=1.17 Hz, 1H) 7.86 (s, 1H)7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H); MS (ESI,m/z): 614.3[M+H]⁺

Example 1602-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and(4-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)boronicacid pinacol ester, the title compound was obtained as described for theexample 134.

MS (ESI, m/z): 656.4 [M+H]⁺

Example 1612-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-(2-(4-methylpiperazino)ethyl)phenylboronic acid pinacol ester,the title compound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.79, 6.75 Hz, 1H)1.74-1.87 (m, 3H) 2.00-2.11 (m, 1H) 2.11-2.23 (m, 1H) 2.79-2.96 (m, 2H)3.02 (br s, 2H) 3.24 (s, 2H) 3.41 (br s, 4H) 3.89 (s, 3H) 3.97-4.03 (m,1H) 4.41 (br s, 1H) 4.61-4.71 (m, 2H) 7.31 (br d, J=8.22 Hz, 2H) 7.40(d, J=7.63 Hz, 2H) 7.50 (br d, J=8.22 Hz, 2H) 7.51-7.57 (m, 2H) 7.84 (brd, J=2.93 Hz, 1H) 7.96 (s, 1H) 8.16-8.21 (m, 1H) 8.50 (br d, J=4.70 Hz,1H);

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1622-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate,the title compound was obtained as described for the example 134 andfollowing deprotection with TFA.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br s, 1H) 1.80 (br d, J=6.65 Hz, 3H)2.03 (br s, 1H) 2.15 (br s, 1H) 2.28 (br d, J=13.69 Hz, 4H) 3.14-3.25(m, 2H) 3.56 (br d, J=11.35 Hz, 2H) 3.90 (s, 3H) 3.97 (br s, 1H) 4.39(br s, 1H) 4.53 (br s, 1H) 4.60 (s, 2H) 7.32 (br d, J=7.83 Hz, 2H) 7.47(br d, J=7.83 Hz, 2H) 7.79 (s, 1H) 7.85 (s, 1H) 7.97 (br s, 2H) 8.20 (brs, 1H) 8.48 (s, 1H);

MS (ESI, m/z): 541.3 [M+H]⁺

Example 1632-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using(1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-piperidine,the title compound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.57-1.66 (m, 1H) 1.72-1.87 (m, 3H) 2.03(br dd, J=12.62, 6.75 Hz, 1H) 2.17 (br s, 1H) 2.24-2.42 (m, 4H) 2.94 (s,3H) 3.19-3.27 (m, 2H) 3.48 (br s, 1H) 3.90 (s, 3H) 3.98 (br d, J=6.46Hz, 1H) 4.36-4.45 (m, 1H) 4.46-4.55 (m, 1H) 4.57-4.64 (m, 2H) 7.33 (brd, J=8.22 Hz, 2H) 7.47 (br d, J=8.22 Hz, 2H) 7.79 (br s, 1H) 7.84 (s,1H) 7.97 (d, J=5.87 Hz, 2H) 8.20 (br d, J=1.76 Hz, 1H) 8.47 (s, 1H); MS(ESI, m/z): 555.3 [M+H]⁺

Example 1642-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (1S,2R)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine and(4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.58-1.69 (m, 1H) 1.82-1.97 (m, 4H)2.00-2.07 (m, 1H) 2.83-2.90 (m, 3H) 3.79 (s, 3H) 3.80-3.87 (m, 2H)4.11-4.18 (m, 1H) 4.36-4.43 (m, 1H) 4.45 (d, J=11.74 Hz, 1H) 4.67 (d,J=11.74 Hz, 1H) 7.38 (d, J=8.22 Hz, 2H) 7.40-7.44 (m, 2H) 7.46 (d,J=8.22 Hz, 2H) 7.49 (d, J=8.22 Hz, 2H) 7.78 (s, 1H) 7.83 (s, 1H)8.12-8.19 (m, 1H) 8.44 (s, 1H); MS (ESI, m/z): 580.3 [M+H]⁺

Example 1652-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (1R,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine and(4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.60-1.70 (m, 1H) 1.81-1.98 (m, 4H)2.00-2.09 (m, 1H) 2.87 (s, 3H) 3.79 (s, 3H) 3.80-3.85 (m, 2H) 4.15 (d,J=4.70 Hz, 1H) 4.36-4.42 (m, 1H) 4.45 (d, J=11.74 Hz, 1H) 4.67 (d,J=12.33 Hz, 1H) 7.38 (d, J=8.22 Hz, 2H) 7.42 (d, J=7.04 Hz, 2H) 7.46 (d,J=8.22 Hz, 2H) 7.48-7.50 (m, 2H) 7.78 (s, 1H) 7.83 (s, 1H) 8.15 (d,J=1.76 Hz, 1H) 8.44 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 580.3 [M+H]⁺

Example 1662-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamide

Using (1S,2S)-2-((4-bromobenzyl)oxy)cyclohexan-1-amine and(4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.43 (br s, 4H) 1.97-2.07 (m, 2H) 2.18 (brs, 2H) 2.32 (s, 3H) 3.40-3.48 (m, 1H) 3.58 (s, 2H) 3.80-3.89 (m, 1H)3.90 (s, 3H) 4.61 (s, 2H) 7.41 (dd, J=14.09, 8.22 Hz, 4H) 7.55-7.62 (m,4H) 7.78 (s, 1H) 7.89 (s, 1H) 8.03 (d, J=1.76 Hz, 1H) 8.23 (br s, 1H);MS (ESI, m/z): 594.4 [M+H]⁺

Example 1672-amino-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid and(4-(2-(4-methylpiperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacolester, the title compound was obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.47 (s, 6H) 1.55-1.70 (m, 1H) 1.82 (br d,J=7.04 Hz, 3H) 2.03 (br s, 1H) 2.12-2.25 (m, 1H) 2.86 (s, 3H) 4.00 (brs, 1H) 4.40 (br s, 1H) 4.66 (s, 2H) 6.90-6.99 (m, 1H) 7.38-7.46 (m, 2H)7.59 (br dd, J=10.96, 7.83 Hz, 6H) 8.01 (d, J=5.09 Hz, 1H) 8.33 (d,J=7.83 Hz, 1H); MS (ESI, m/z): 528.3 [M+H]⁺

Example 1682-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid,(1S,2S)-2-((4-bromo-2-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amineand 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, thetitle compound was obtained as described for the example 134.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.66 (dt, J=13.60, 6.70 Hz, 1H) 1.78-1.93(m, 3H) 1.97-2.12 (m, 1H) 2.13-2.26 (m, 1H) 2.87 (s, 3H) 3.77 (s, 2H)4.00-4.05 (m, 1H) 4.43 (br dd, J=10.76, 7.63 Hz, 1H) 6.98 (dd, J=7.43,6.26 Hz, 1H) 7.48 (d, J=8.22 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.77-7.93(m, 3H) 8.02 (br dd, J=6.26, 1.57 Hz, 1H) 8.37 (dd, J=7.43, 1.57 Hz,1H):

MS (ESI, m/z): 568.3[M+H]⁺

Example 169amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3-yl)methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 169:

Intermediate 5

To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine(0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol)followed by (1S,2S)-2-((3-bromobenzyl)oxy)cyclopentan-1-amine (475 mg,1.76 mmol). The mixture was stirred at room temperature for 1 hr andthen saturated sodium bicarbonate solution was added. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified through silicagelcolumn chromatography to give 680 mg of off-white solid.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.69 (m, 1H) 1.72-1.88 (m, 3H)1.96-2.08 (m, 1H) 2.16 (td, J=13.35, 7.92 Hz, 1H) 3.86-4.00 (m, 3H) 4.39(td, J=7.48, 4.40 Hz, 1H) 4.60 (q, J=12.72 Hz, 2H) 7.20 (t, J=7.92 Hz,1H) 7.29 (d, J=7.63 Hz, 1H) 7.35 (d, J=7.63 Hz, 1H) 7.50 (s, 1H)7.45-7.53 (m, 1H) 7.86 (s, 1H) 8.00 (s, 1H) 8.23 (d, J=2.35 Hz, 1H) 8.46(d, J=1.76 Hz, 1H):

MS (ESI, m/z): 470.1/472.1 [M+H]⁺

Example 1692-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 5 (33 mg, 0.07 mmol) and(3-hydroxyphenyl)boronic acid (11 mg, 0.08 mmol) in 0.4 ml of1,4-dioxane/water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed byPd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C.for 3 hrs, cooled to room temperature, and extracted with EtOAc, driedover anhydrous MgSO₄ and concentrated under vacuum. The crude residuewas dissolved with 0.5 ml of CH₂Cl₂/TFA (10/1) and the mixture wasstirred for 2 hrs. After concentration under vacuum, the crude residuewas purified by preparative HPLC to afford 27 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=12.62, 6.75 Hz, 1H) 1.81(br d, J=4.70 Hz, 3H) 2.03 (br d, J=11.74 Hz, 1H) 2.16 (br s, 1H) 3.92(s, 3H) 3.94-4.01 (m, 1H) 4.43 (br s, 1H) 4.64-4.74 (m, 2H) 7.13 (br d,J=6.46 Hz, 2H) 7.34-7.43 (m, 3H) 7.47 (br d, J=7.63 Hz, 2H) 7.58-7.62(m, 1H) 7.81 (s, 1H) 7.96 (s, 1H) 8.17 (br d, J=1.76 Hz, 1H) 8.36 (br d,J=2.35 Hz, 1H); MS (ESI, m/z): 484.2 [M+H]⁺

Example 1702-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-3-yl)methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-aminophenyl)boronic acid, the title compound was obtained asdescribed for the example 169.

MS (ESI, m/z): 483.2 [M+H]⁺

Example 1712-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(hydroxymethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 169.

MS (ESI, m/z): 498.2 [M+H]⁺

Example 1722-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 172:

Intermediate 6

To a mixture of intermediate 4 (33 mg, 0.07 mmol) and(4-formylphenyl)boronic acid (12 mg, 0.08 mmol) in 0.4 ml of1,4-dioxane/water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed byPd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C.for 3 hrs, cooled to room temperature, and extracted with EtOAc, driedover anhydrous MgSO₄. After concentration under vacuum, the cruderesidue was purified by preparative HPLC to afford 30 mg of the titlecompound.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.52-1.62 (m, 1H) 1.74-1.85 (m, 3H)1.85-1.93 (m, 1H) 1.97-2.06 (m, 1H) 2.27 (br dd, J=13.30, 5.48 Hz, 1H)3.87 (s, 3H) 3.97-4.03 (m, 1H) 4.36-4.46 (m, 1H) 4.69 (s, 2H) 6.90 (brs, 1H) 7.12 (br s, 1H) 7.16-7.19 (m, 1H) 7.43-7.48 (m, 2H) 7.50 (s, 1H)7.54-7.60 (m, 2H) 7.68 (m, J=8.22 Hz, 2H) 7.79 (s, 1H) 7.90 (m, J=8.22Hz, 2H) 7.98 (s, 1H) 10.02 (s, 1H); MS (ESI, m/z): 496.2 [M+H]⁺

Example 1722-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To intermediate 6 (30 mg, 0.06 mmol) in 0.4 ml of dichloroethane wasadded 1-methylpiperazine (12 mg, 0.12 mmol) followed by NaBH(OAc)₃ (26mg, 0.18 mmol). The mixture was stirred at room temperature for 4 hr andthen water was added. The mixture was extracted with EtOAc, washed withbrine, dried over MgSO₄. After concentration under vacuum, the cruderesidue was purified by preparative HPLC to afford 27 mg of the titlecompound.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.52-1.67 (m, 1H) 1.69-1.86 (m, 3H) 2.01(br dd, J=12.52, 5.87 Hz, 1H) 2.08-2.21 (m, 1H) 2.28 (s, 3H) 2.51 (br s,8H) 3.54 (s, 2H) 3.84 (s, 3H) 3.91-3.99 (m, 1H) 4.40 (br d, J=4.70 Hz,1H) 4.64 (br d, J=3.13 Hz, 2H) 7.34 (br d, J=7.83 Hz, 2H) 7.39 (br d,J=8.22 Hz, 2H) 7.47 (br d, J=7.83 Hz, 1H) 7.50 (br d, J=7.83 Hz, 2H)7.73 (s, 1H) 7.81 (s, 1H) 7.96 (s, 1H) 8.23 (s, 1H); MS (ESI, m/z):580.3 [M+H]⁺

Example 1732-amino-N-((1S,2S)-2-((4′-(((2-hydroxyethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-aminoethan-1-ol, the title compound was obtained as describedfor the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.59-1.69 (m, 1H) 1.74-1.88 (m, 3H)1.99-2.11 (m, 1H) 2.18 (td, J=12.91, 7.04 Hz, 1H) 3.11-3.12 (m, 1H)3.11-3.16 (m, 1H) 3.77-3.86 (m, 2H) 3.90 (s, 3H) 3.93 (br d, J=5.87 Hz,1H) 3.97-4.05 (m, 1H) 4.26 (s, 2H) 4.39-4.48 (m, 1H) 4.67 (s, 2H) 7.44(d, J=8.22 Hz, 2H) 7.53 (m, J=8.22 Hz, 2H) 7.55-7.62 (m, 2H) 7.66 (d,J=8.22 Hz, 2H) 7.85 (s, 1H) 7.97 (s, 1H) 8.20 (s, 1H) 8.49 (br s, 1H);

MS (ESI, m/z): 541.3 [M+H]⁺

Example 1742-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using morpholine, the title compound was obtained as described for theexample 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.57-1.69 (m, 1H) 1.74-1.90 (m, 3H) 2.04(s, 1H) 2.14-2.23 (m, 1H) 2.19 (br d, J=7.63 Hz, 1H) 3.31-3.46 (m, 2H)3.90 (s, 3H) 3.99-4.03 (m, 1H) 4.39 (s, 2H) 4.42 (br d, J=5.28 Hz, 1H)4.67 (d, J=3.52 Hz, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H)7.59 (d, J=8.22 Hz, 2H) 7.71 (d, J=7.63 Hz, 2H) 7.85 (s, 1H) 7.98 (s,1H) 8.21 (d, J=1.76 Hz, 1H) 8.49 (br s, 1H);

MS (ESI, m/z): 567.3 [M+H]⁺

Example 1752-amino-N-((1S,2S)-2-((4′-((4-(3,3-difluoropiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3,3-difluoropiperidine, the title compound was obtained asdescribed for the example 172.

MS (ESI, m/z): 601.3 [M+H]⁺

Example 1762-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-methylpiperidine, the title compound was obtained as describedfor the example 172.

MS (ESI, m/z): 579.3 [M+H]⁺

Example 1772-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using piperazine, the title compound was obtained as described for theexample 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.50, 7.04 Hz, 1H)1.73-1.88 (m, 3H) 2.00-2.08 (m, 1H) 2.13-2.22 (m, 1H) 2.96 (br s, 4H)3.32 (br d, J=9.98 Hz, 4H) 3.50 (s, 1H) 3.84-3.89 (m, 2H) 3.90 (s, 3H)4.00 (br s, 1H) 4.38-4.44 (m, 1H) 4.66 (d, J=2.93 Hz, 2H) 7.38-7.47 (m,4H) 7.52-7.60 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (d, J=2.35 Hz, 1H)8.50 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 566.3 [M+H]⁺

Example 1782-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-phenylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 1-phenylpiperazine, the title compound was obtained as describedfor the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.61-1.69 (m, 1H) 1.76-1.87 (m, 3H)2.00-2.07 (m, 1H) 2.15-2.23 (m, 1H) 3.90 (s, 3H) 3.98-4.04 (m, 1H)4.39-4.44 (m, 1H) 4.45 (s, 2H) 4.68 (s, 2H) 6.92 (t, J=7.34 Hz, 1H) 7.00(d, J=8.22 Hz, 2H) 7.27 (t, J=7.92 Hz, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.60(dd, J=9.68, 8.51 Hz, 4H) 7.72 (br d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98(s, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.51 (d, J=1.76 Hz, 1H); MS (ESI, m/z):642.4 [M+H]⁺

Example 1792-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using 4-(pyrrolidin-1-yl)piperidine, the title compound was obtained asdescribed for the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.60-1.69 (m, 1H) 1.74-1.88 (m, 3H)1.96-2.23 (m, 8H) 2.43 (br d, J=13.50 Hz, 2H) 3.06-3.21 (m, 4H) 3.44 (brs, 2H) 3.66 (br d, J=12.91 Hz, 4H) 3.90 (s, 3H) 3.99-4.03 (m, 1H) 4.37(s, 2H) 4.39-4.45 (m, 1H) 4.67 (s, 2H) 7.41-7.48 (m, 2H) 7.51-7.57 (m,2H) 7.58 (d, J=8.22 Hz, 2H) 7.68 (br d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98(s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.50 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 634.4 [M+H]⁺

Example 1802-amino-N-((1S,2S)-2-((4′-((4-hydroxypiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using piperidin-4-ol, the title compound was obtained as described forthe example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.59-1.68 (m, 1H) 1.74-1.87 (m, 3H) 1.92(br s, 1H) 2.03 (dt, J=13.35, 6.53 Hz, 1H) 2.10-2.23 (m, 1H) 3.07 (br s,1H) 3.51 (br d, J=10.56 Hz, 1H) 3.82 (br s, 1H) 3.89-3.92 (m, 3H)3.98-4.03 (m, 1H) 4.08 (br s, 1H) 4.34 (br s, 2H) 4.39-4.45 (m, 1H) 4.67(s, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.54 (br s, 2H) 7.57-7.61 (m, 2H) 7.59(d, J=8.22 Hz, 2H) 7.69 (br d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.99 (s, 1H)8.21 (s, 1H) 8.52 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 581.3 [M+H]⁺

Example 1812-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained asdescribed for the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.50, 7.04 Hz, 1H)1.76-1.86 (m, 3H) 2.00-2.08 (m, 1H) 2.14-2.22 (m, 1H) 3.19 (br s, 2H)3.82-3.85 (m, 2H) 3.90 (s, 3H) 3.98-4.02 (m, 1H) 4.39-4.44 (m, 1H) 4.66(s, 2H) 7.40-7.47 (m, 4H) 7.53-7.61 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H)8.20 (d, J=2.35 Hz, 1H) 8.52 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 610.3 [M+H]⁺

Example 1822-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxy-2-methylpropyl)-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-methyl-1-(piperazin-1-yl)propan-2-ol, the title compound wasobtained as described for the example 172.

MS (ESI, m/z): 638.4 [M+H]⁺

Example 1832-amino-N-((1S,2S)-2-((4′-((4-ethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-ethylpiperazine, the title compound was obtained as describedfor the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.32 (t, J=7.34 Hz, 3H) 1.59-1.68 (m, 1H)1.74-1.88 (m, 3H) 2.04 (dq, J=13.50, 6.85 Hz, 1H) 2.13-2.21 (m, 1H) 3.18(br d, J=7.63 Hz, 2H) 3.78-3.87 (m, 2H) 3.90 (s, 3H) 3.98-4.02 (m, 1H)4.38-4.44 (m, 1H) 4.66 (d, J=1.76 Hz, 2H) 7.38-7.46 (m, 4H) 7.51-7.60(m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (d, J=2.35 Hz, 1H) 8.51 (d,J=2.35 Hz, 1H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 1842-amino-N-((1S,2S)-2-((4′-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-cyclopropylpiperazine, the title compound was obtained asdescribed for the example 172.

MS (ESI, m/z): 606.4 [M+H]⁺

Example 1852-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((R)-3-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using tert-butyl(R)-2-methylpiperazine-1-carboxylate, the title compoundwas obtained as described for the example 172 and following deprotectionwith TFA.

MS (ESI, m/z): 580.3 [M+H]⁺

Example 1862-amino-N-((1S,2S)-2-((4′-(((R)-3,4-dimethylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (R)-1,2-dimethylpiperazine, the title compound was obtained asdescribed for the example 172.

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1872-amino-N-((1S,2S)-2-((4′-(((R)-2,4-dimethylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (R)-1,3-dimethylpiperazine, the title compound was obtained asdescribed for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.34 (br d, J=5.09 Hz, 3H) 1.63 (br dd,J=15.06, 6.46 Hz, 1H) 1.81 (br d, J=7.43 Hz, 3H) 2.03 (br d, J=6.26 Hz,1H) 2.18 (s, 1H) 2.55 (br s, 1H) 2.82 (s, 3H) 2.92 (br s, 1H) 3.02 (brd, J=12.52 Hz, 1H) 3.89 (s, 3H) 4.00 (br s, 1H) 4.30 (br d, J=11.35 Hz,1H) 4.42 (br s, 1H) 4.65 (s, 2H) 7.41 (br d, J=7.43 Hz, 4H) 7.54 (br dd,J=7.63, 3.33 Hz, 4H) 7.84 (s, 1H) 7.96 (s, 1H) 8.19 (s, 1H) 8.50 (s,1H);

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1882-amino-N-((1S,2S)-2-((4′-((3-ethyl-4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using 2-ethyl-1-methylpiperazine, the title compound was obtained asdescribed for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 0.96 (br t, J=7.24 Hz, 3H) 1.62 (br d,J=14.48 Hz, 3H) 1.81 (br d, J=7.43 Hz, 3H) 1.92 (br s, 1H) 2.04 (br s,1H) 2.16 (br d, J=7.04 Hz, 1H) 2.87 (s, 3H) 3.20 (br d, J=14.09 Hz, 1H)3.45 (br d, J=13.30 Hz, 1H) 3.70 (br d, J=13.30 Hz, 1H) 3.81 (br d,J=12.91 Hz, 1H) 3.89 (s, 3H) 3.99 (br s, 1H) 4.42 (br s, 1H) 4.65 (s,2H) 7.41 (br d, J=8.22 Hz, 4H) 7.55 (br d, J=7.43 Hz, 4H) 7.85 (s, 1H)7.97 (s, 1H) 8.19 (s, 1H) 8.51 (s, 1H);

MS (ESI, m/z): 608.4 [M+H]⁺

Example 1892-amino-N-((1S,2S)-2-((4′-((cis-3,5-dimethylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate, the titlecompound was obtained as described for the example 172 and followingdeprotection with TFA.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.27 (br d, J=6.26 Hz, 6H) 1.64 (br d,J=5.87 Hz, 1H) 1.81 (br d, J=7.04 Hz, 3H) 1.96-2.24 (m, 3H) 3.09 (d,J=12.91 Hz, 2H) 3.62 (br s, 5H) 3.68 (s, 3H) 3.89 (s, 3H) 4.00 (br s,1H) 4.37-4.45 (m, 1H) 4.65 (s, 2H) 7.34-7.46 (m, 4H) 7.53 (br d, J=7.43Hz, 4H) 7.83 (s, 1H) 7.95 (s, 1H) 8.20 (s, 1H) 8.45 (s, 1H);

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1902-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using cis-1,2,6-trimethylpiperazine, the title compound was obtained asdescribed for the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.30 (br d, J=6.46 Hz, 6H) 1.64 (br dd,J=13.50, 7.04 Hz, 1H) 1.74-1.90 (m, 3H) 2.00-2.09 (m, 1H) 2.18 (br dd,J=12.91, 5.87 Hz, 1H) 2.30 (br d, J=12.91 Hz, 3H) 3.22 (br s, 3H) 3.45(br s, 2H) 3.84 (br d, J=19.37 Hz, 2H) 3.90 (s, 3H) 3.97-4.03 (m, 1H)4.38-4.45 (m, 1H) 4.66 (s, 2H) 4.69 (s, 1H) 7.42 (br d, J=7.63 Hz, 4H)7.49-7.62 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.52(d, J=1.76 Hz, 1H); MS (ESI, m/z): 608.4 [M+H]⁺

Example 1912-amino-N-((1S,2S)-2-((4′-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2,5-dimethylpiperazine, the title compound was obtained asdescribed for the example 172.

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1922-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using trans-1,2,5-trimethylpiperazine, the title compound was obtainedas described for the example 172.

MS (ESI, m/z): 608.4 [M+H]⁺

Example 1932-amino-N-((1S,2S)-2-((4′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using N,N-Dimethyl-3-pyrrolidinamine, the title compound was obtained asdescribed for the example 172.

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1943-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid,the title compound was obtained as described for the example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.60-1.69 (m, 1H) 1.70-1.78 (m, 1H)1.78-1.87 (m, 2H) 2.03-2.20 (m, 3H) 2.88 (d, J=1.76 Hz, 3H) 3.00 (br s,4H) 3.34 (br d, J=11.74 Hz, 3H) 3.85 (s, 3H) 3.91 (br d, J=11.74 Hz, 2H)3.99-4.06 (m, 1H) 4.33-4.40 (m, 1H) 4.59-4.70 (m, 2H) 7.38 (d, J=8.22Hz, 2H) 7.42 (br d, J=8.22 Hz, 2H) 7.47 (d, J=8.22 Hz, 2H) 7.52 (br d,J=8.22 Hz, 2H) 7.99 (s, 1H) 8.12 (s, 1H) 8.41 (s, 1H);

MS (ESI, m/z): 581.3 [M+H]⁺

Example 1952-amino-N-((1S,2S)-2-((3′-fluoro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (3-fluoro-4-formylphenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.69, 7.04 Hz, 1H)1.72-1.90 (m, 3H) 1.96-2.09 (m, 1H) 2.10-2.23 (m, 1H) 2.90 (s, 3H)3.05-3.27 (m, 4H) 3.34-3.51 (m, 4H) 3.89 (s, 3H) 3.94-4.01 (m, 1H) 4.07(s, 2H) 4.34-4.47 (m, 1H) 4.60-4.73 (m, 2H) 5.47 (s, 1H) 7.35 (br d,J=11.35 Hz, 1H) 7.42 (br d, J=7.83 Hz, 3H) 7.50 (br t, J=7.83 Hz, 1H)7.55 (d, J=8.22 Hz, 2H) 7.83 (s, 1H) 7.97 (s, 1H) 8.17 (d, J=1.96 Hz,1H) 8.50 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 598.7 [M+H]⁺

Example 1962-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using ((3,5-difluoro-4-formylphenyl)boronic acid pinacol ester, thetitle compound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.30, 7.04 Hz, 1H)1.71-1.91 (m, 3H) 2.03 (br dd, J=12.91, 5.48 Hz, 1H) 2.12-2.23 (m, 1H)2.87 (s, 3H) 2.94 (br d, J=18.00 Hz, 3H) 3.32 (br s, 4H) 3.90 (s, 3H)3.99 (br s, 1H) 4.40 (br d, J=3.91 Hz, 1H) 4.62-4.77 (m, 2H) 7.24 (br d,J=8.61 Hz, 2H) 7.44 (m, J=7.83 Hz, 2H) 7.57 (m, J=7.83 Hz, 2H) 7.83 (s,1H) 7.98 (s, 1H) 8.19 (s, 1H) 8.50 (s, 1H);

MS (ESI, m/z): 616.8 [M+H]⁺

Example 1972-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.59-1.71 (m, 1H) 1.75-1.89 (m, 3H)1.99-2.10 (m, 1H) 2.13-2.25 (m, 1H) 2.91 (s, 3H) 3.47 (br d, J=1.57 Hz,2H) 3.81 (s, 2H) 3.91 (s, 3H) 4.02 (br d, J=4.30 Hz, 1H) 4.39-4.46 (m,1H) 4.69 (s, 2H) 7.47 (m, J=8.22 Hz, 2H) 7.60 (m, J=8.22 Hz, 2H) 7.83(d, J=8.22 Hz, 4H) 7.98 (s, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.50 (d, J=2.35Hz, 1H);

MS (ESI, m/z): 648.32 [M+H]⁺

Example 1982-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-methyl-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using (4-formyl-3-methylphenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.11, 6.85 Hz, 2H)1.72-1.90 (m, 3H) 1.82 (br s, 1H) 1.94-2.09 (m, 2H) 2.10-2.24 (m, 2H)2.43 (s, 1H) 2.88 (s, 3H) 3.29-3.31 (m, 11H) 3.69 (s, 1H) 3.90 (s, 2H)3.93-3.96 (m, 1H) 4.01 (br d, J=4.70 Hz, 1H) 4.16 (s, 1H) 4.37-4.47 (m,1H) 4.66 (d, J=3.13 Hz, 1H) 7.37-7.43 (m, 2H) 7.51-7.55 (m, 1H)7.52-7.59 (m, 1H) 7.85 (d, J=0.78 Hz, 1H) 7.96 (s, 1H) 8.19 (d, J=1.96Hz, 1H) 8.49 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 594.4 [M+H]⁺

Example 1992-amino-N-((1S,2S)-2-((3′-hydroxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-formyl-3-hydroxyphenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br dd, J=12.72, 6.85 Hz, 1H)1.74-1.90 (m, 3H) 2.05 (br s, 1H) 2.12-2.26 (m, 1H) 2.82 (d, J=3.13 Hz,3H) 3.13 (br s, 5H) 3.91 (s, 3H) 4.01 (br d, J=6.26 Hz, 1H) 4.05 (s, 1H)4.08 (s, 1H) 4.38-4.46 (m, 1H) 4.66 (s, 2H) 7.05 (s, 1H) 7.28 (br d,J=8.61 Hz, 1H) 7.25-7.34 (m, 1H) 7.32 (br d, J=7.83 Hz, 1H) 7.41 (d,J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.54-7.59 (m, 1H) 7.85 (s, 1H)7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 596.3 [M+H]⁺

Example 2002-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-nitro-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamide

Using (4-formyl-3-nitrophenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (dt, J=13.89, 7.14 Hz, 1H) 1.74-1.91(m, 3H) 2.00-2.10 (m, 1H) 2.13-2.24 (m, 1H) 2.88 (s, 3H) 3.35-3.39 (m,2H) 3.91 (s, 3H) 3.92-3.95 (m, 2H) 3.99-4.03 (m, 1H) 4.39-4.47 (m, 1H)4.69 (d, J=3.13 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.60-7.65 (m, 4H) 7.83(s, 1H) 7.97 (s, 1H) 8.02 (d, J=1.96 Hz, 1H) 8.21 (d, J=2.35 Hz, 1H)8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 625.3 [M+H]⁺

Example 2012-amino-N-((1S,2S)-2-((3′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-formyl-3-methoxyphenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (br dd, J=13.50, 6.46 Hz, 1H)1.74-1.91 (m, 3H) 1.99-2.10 (m, 1H) 2.19 (br d, J=6.65 Hz, 1H) 2.81 (s,3H) 3.91 (s, 3H) 3.92 (s, 3H) 3.98-4.07 (m, 1H) 4.43 (br d, J=3.52 Hz,1H) 4.68 (s, 2H) 7.15-7.24 (m, 2H) 7.37-7.47 (m, 3H) 7.59 (d, J=8.22 Hz,2H) 7.86 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.51 (d, J=2.35Hz, 1H);

MS (ESI, m/z): 610.3 [M+H]⁺

Example 2022-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (2-chloro-4-formylphenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

MS (ESI, m/z): 614.3 [M+H]⁺

Example 2032-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using ((6-formylpyridin-3-yl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (dt, J=13.60, 7.09 Hz, 1H) 1.74-1.90(m, 3H) 2.05 (br dd, J=13.11, 6.46 Hz, 1H) 2.13-2.26 (m, 1H) 2.90 (s,3H) 3.91-3.94 (m, 3H) 3.99-4.06 (m, 1H) 4.43 (br dd, J=11.93, 6.85 Hz,1H) 7.52 (d, J=8.22 Hz, 2H) 7.64-7.68 (m, 2H) 7.72 (br dd, J=12.33, 8.41Hz, 2H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.51 (d,J=1.96 Hz, 1H) 8.82 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 581.3 [M+H]⁺

Example 2042-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (5-formylpyridin-2-yl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.66 (td, J=14.09, 7.04 Hz, 1H) 1.76-1.92(m, 3H) 1.98-2.11 (m, 1H) 2.19 (br s, 1H) 2.90 (s, 3H) 3.64 (s, 1H) 3.76(s, 3H) 3.98-4.07 (m, 1H) 4.38-4.48 (m, 1H) 7.52 (d, J=8.22 Hz, 2H) 7.84(s, 1H) 7.90 (dd, J=8.41, 1.76 Hz, 3H) 7.98 (s, 1H) 8.02 (br d, J=8.61Hz, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.50 (d, J=1.96 Hz, 1H) 8.60 (s, 1H);

MS (ESI, m/z): 581.3 [M+H]⁺

Example 2052-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester and2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained asdescribed for the example 11′)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.57-1.72 (m, 1H) 1.75-1.90 (m, 3H) 2.04(dt, J=12.81, 6.70 Hz, 1H) 2.13-2.26 (m, 1H) 3.82 (s, 2H) 3.86-3.90 (m,2H) 3.91 (s, 3H) 3.97-4.05 (m, 1H) 4.43 (br dd, J=11.93, 6.46 Hz, 1H)4.69 (s, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.60 (d, J=8.22 Hz, 2H) 7.81-7.87(m, 3H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 678.3[M+H]⁺

Example 2062-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-(2-hydroxyethyl)-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2-chloro-4-formylphenyl)boronic acid pinacol ester and2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained asdescribed for the example 172.

MS (ESI, m/z): 644.3 [M+H]⁺

Example 2072-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid and(4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, thetitle compound was obtained as described for the example 172.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.53-1.69 (m, 1H) 1.76-1.89 (m, 3H) 2.01(s, 1H) 2.18 (br dd, J=13.30, 5.87 Hz, 1H) 2.48 (br s, 2H) 2.91 (s, 3H)3.82 (s, 2H) 3.99 (br d, J=4.30 Hz, 1H) 4.40 (br d, J=5.09 Hz, 1H) 4.68(d, J=4.30 Hz, 2H) 6.95 (dd, J=7.43, 6.26 Hz, 1H) 7.47 (d, J=8.22 Hz,2H) 7.62 (d, J=8.22 Hz, 2H) 7.84-7.92 (m, 3H) 7.98-8.05 (m, 1H) 8.32(dd, J=7.43, 1.56 Hz, 1H);

MS (ESI, m/z): 568.3 [M+H]⁺

Example 2082-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 208:

Intermediate 7

To a mixture of intermediate 4 (100 mg, 0.21 mmol) and(4-acetylphenyl)boronic acid (52 mg, 0.32 mmol) in 1.2 ml of1,4-dioxane/water (3/1) was added K₂CO₃ (88 mg, 0.64 mmol) followed byPd(PPh₃)₄ (12 mg, 0.01 mmol). The reaction mixture was heated at 100° C.for 3 hrs, cooled to room temperature, and extracted with EtOAc, driedover anhydrous MgSO₄. After concentration under vacuum, the crudeproduct was purified by silicagel column chromatography to give 80 mg ofoff-white solid

¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1H)1.74-1.88 (m, 3H) 2.05 (br dd, J=12.62, 7.34 Hz, 1H) 2.17 (br dd,J=13.21, 5.58 Hz, 1H) 2.62 (s, 3H) 3.89 (s, 3H) 3.96-4.01 (m, 1H)4.38-4.45 (m, 1H) 4.61-4.73 (m, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.60 (d,J=8.22 Hz, 2H) 7.66 (d, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.94 (s, 1H) 8.01(d, J=8.22 Hz, 2H) 8.18 (d, J=1.76 Hz, 1H) 8.44 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 510.8[M+H]⁺

Example 2082-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′41-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To a mixture of intermediate 7 (30 mg, 0.06 mmol) in 0.4 ml of methanolwas added 1-methylpiperazine (14 μl, 0.12 mmol) followed by NaBH₃CN (11mg, 0.18 mmol). The mixture was stirred at room temperature for 4 hr andthen water was added. The mixture was extracted with EtOAc, washed withbrine, dried over MgSO₄. After concentration under vacuum, the cruderesidue was purified by preparative HPLC to afford 17 mg of the titlecompound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.40 (d, J=6.46 Hz, 3H) 1.59 (br dd,J=13.21, 7.34 Hz, 1H) 1.73-1.85 (m, 3H) 1.98-2.05 (m, 1H) 2.15 (br dd,J=13.21, 5.58 Hz, 1H) 2.31 (s, 3H) 2.35-2.77 (m, 8H) 3.41-3.48 (m, 1H)3.86 (s, 3H) 3.90-3.99 (m, 1H) 4.37-4.44 (m, 1H) 4.61-4.70 (m, 2H) 7.34(d, J=7.63 Hz, 2H) 7.39 (br d, J=7.63 Hz, 2H) 7.48 (br d, J=7.63 Hz, 2H)7.50 (br d, J=8.22 Hz, 2H) 7.74 (s, 1H) 7.82 (d, J=2.93 Hz, 1H) 7.96 (s,1H) 8.22-8.26 (m, 1H);

MS (ESI, m/z): 594.7 [M+H]⁺

Example 2092-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamide

Using (2S,6R)-1,2,6-trimethylpiperazine, title compound was obtained asdescribed for the example 208.

MS (ESI, m/z): 622.4 [M+H]⁺

Example 2102-amino-N-((1S,2S)-2-((4′41-(4-(2-hydroxyethyl)piperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using 1-(2-hydroxyethyl)piperazine, title compound was obtained asdescribed for the example 208.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.50, 7.04 Hz, 1H) 1.69(d, J=7.04 Hz, 3H) 1.75-1.88 (m, 3H) 2.00-2.08 (m, 1H) 2.18 (br dd,J=13.50, 5.87 Hz, 1H) 3.16-3.23 (m, 2H) 3.23-3.27 (m, 2H) 3.53 (br s,4H) 3.84 (br t, J=4.99 Hz, 2H) 3.90 (s, 3H) 3.98-4.03 (m, 1H) 4.25 (brd, J=7.04 Hz, 1H) 4.38-4.45 (m, 1H) 4.64-4.70 (m, 2H) 7.43 (d, J=7.63Hz, 2H) 7.51 (m, J=8.22 Hz, 2H) 7.56 (m, J=8.22 Hz, 2H) 7.64 (d, J=8.22Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.19 (s, 1H) 8.53 (s, 1H);

MS (ESI, m/z): 624.4 [M+H]⁺

Example 2112-amino-N-((1S,2S)-2-((4′-((1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-(cis-2,6-dimethylpiperazin-1-yl)ethan-1-ol, title compound wasobtained as described for the example 208.

MS (ESI, m/z): 652.4 [M+H]⁺

Example 2122-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-acetyl-3,5-difluorophenyl)boronic acid pinacol ester and2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained asdescribed for the example 208.

MS (ESI, m/z): 660.32 [M+H]⁺

Scheme for the preparation of the intermediate 9:

Intermediate 8

A mixture of (S)-1-(4-Bromophenyl)ethylamine (300 mg, 1.50 mmol) and(N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (533 mg, 1.80 mmol)in 3 ml of DIPEA was heated at 120° C. for 24 hrs, cooled to roomtemperature, and extracted with EtOAc, dried over anhydrous MgSO₄. Afterconcentration under vacuum, the crude product was purified by silicagelcolumn chromatography to give 500 mg of off-white solid

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.46 Hz, 3H) 2.27-2.33 (m,2H) 2.39 (s, 5H) 2.78 (br s, 4H) 3.37-3.44 (m, 1H) 7.16 (d, J=7.87 Hz,2H) 7.43 (t, J=7.59 Hz, 4H) 7.55-7.60 (m, 2H):

MS (ESI, m/z): 423.1/425.2[M+H]⁺

Intermediate 9 (S)-1-(1-(4-bromophenyl)ethyl)piperazine

Intermediate 8 (0.5 g, 1.1 mmol) in 5 ml of HBr in AcOH was stirred atroom temperature for 24 hrs. After concentration under vacuum, the crudeproduct was diluted with EtOAC and the solid was collected by filtrationto give 0.5 g of off-white solid

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.63 (br s, 3H) 3.40 (br s, 1H)3.47-3.72 (br s, 8H) 7.54 (br s, 2H) 7.69 (br d, J=7.63 Hz, 2H);

MS (ESI, m/z): 269.1/271.4 [M+H]⁺

Intermediate 10 (R)-1-(1-(4-bromophenyl)ethyl)piperazine

Using (R)-1-(4-Bromophenyl)ethylamine, the title compound was obtainedas described for the intermediate 9.

MS (ESI, m/z): 269.1/271.4 [M+H]⁺

Intermediate 11 1-(1-(4-bromophenyl)cyclopropyl)piperazine

Using 1-(4-Bromophenyl)cyclopropan-1-amine, the title compound wasobtained as described for the intermediate 9.

MS (ESI, m/z): 281.1/283.4 [M+H]⁺

Intermediate 12 1-(2-(4-bromophenyl)propan-2-yl)piperazine

Using 2-(4-Bromophenyl)propan-2-amine, the title compound was obtainedas described for the intermediate 9.

MS (ESI, m/z): 283.1/285.4 [M+H]⁺

Example 213 and 214

Scheme for the preparation of the Compounds of Example 213 and 214;

Intermediate 13

To a mixture of intermediate 4 (0.56 g, 1.19 mmol) andbis(pinacalato)diboron (0.6 g, 2.38 mmol) in 6 ml of 1,4-dioxane wasadded KOAc (0.35 g, 3.57 mmol) followed by Pd(PPh₃)₄ (69 mg, 0.06 mmol).The reaction mixture was heated at 110° C. for 5 hrs, cooled to roomtemperature, and partitioned between water and EtOAc, dried overanhydrous MgSO₄. After concentration under vacuum, the crude product waspurified by silicagel column chromatography to give 0.5 g of lightyellow solid

¹H NMR (400 MHz, CD₃OD) δ ppm 1.19 (s, 6H) 1.30 (s, 6H) 1.60 (br dd,J=13.30, 7.04 Hz, 1H) 1.68-1.88 (m, 3H) 1.93-2.06 (m, 1H) 2.15 (br dd,J=13.11, 6.06 Hz, 1H) 3.90 (s, 3H) 3.92-3.99 (m, 1H) 4.32-4.44 (m, 1H)4.64 (s, 2H) 7.33 (m, J=7.83 Hz, 2H) 7.66 (m, J=7.83 Hz, 2H) 7.75 (s,1H) 7.85 (s, 1H) 7.97 (d, J=1.96 Hz, 1H) 8.20-8.30 (m, 1H);

MS (ESI, m/z): 518.3 [M+H]⁺

Example 2132-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To a mixture of intermediate 13 (150 mg, 0.29 mmol) and intermediate 10(100 mg, 0.29 mmol) in 1.5 ml of 1,4-dioxane/water (3/1) was added K₂CO₃(120 mg, 0.87 mmol) followed by Pd(PPh₃)₄ (17 mg, 0.01 mmol). Thereaction mixture was heated at 100° C. for 3 hrs, cooled to roomtemperature, and extracted with EtOAc, dried over anhydrous MgSO₄. Afterconcentration under vacuum, the crude product was purified by silicagelcolumn chromatography to give 130 mg of off-white solid

¹H NMR (600 MHz, CD₃OD) δ ppm 1.40 (d, J=6.46 Hz, 3H) 1.54-1.63 (m, 1H)1.73-1.86 (m, 3H) 1.98-2.05 (m, 1H) 2.12-2.19 (m, 1H) 2.40 (br s, 2H)2.82 (t, J=4.99 Hz, 4H) 3.40 (q, J=6.46 Hz, 1H) 3.86 (s, 3H) 3.95 (dt,J=6.90, 4.48 Hz, 1H) 4.41 (td, J=7.63, 4.70 Hz, 1H) 4.61-4.70 (m, 2H)5.48 (s, 1H) 7.33 (d, J=8.22 Hz, 2H) 7.39 (d, J=8.22 Hz, 2H) 7.44-7.49(m, 2H) 7.49-7.55 (m, 2H) 7.74 (s, 1H) 7.83 (s, 1H) 7.97 (d, J=2.35 Hz,1H) 8.23 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 580.6[M+H]⁺

Example 2142-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To compound 213 (20 mg, 0.03 mmol) in 0.2 ml of 1,2-dichloroethane wasadded formaldehyde (0.005 ml, 0.06 mmol) followed by NaBH(OAc)₃ (13 mg,0.09 mmol). The mixture was stirred at room temperature for 1 hr andthen water was added. The mixture was extracted with EtOAc, washed withbrine, dried over MgSO₄, and concentrated in vacuo. The crude residuewas purified by preparative HPLC to afford 15 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (dd, J=13.50, 7.04 Hz, 1H) 1.71 (d,J=7.04 Hz, 3H) 1.75-1.88 (m, 3H) 2.00-2.10 (m, 1H) 2.12-2.23 (m, 1H)2.91 (s, 3H) 3.20-3.28 (m, 2H) 3.52 (br s, 4H) 3.90 (s, 3H) 4.00 (dt,J=6.46, 4.40 Hz, 1H) 4.32 (q, J=6.65 Hz, 1H) 4.42 (td, J=7.34, 4.11 Hz,1H) 4.63-4.71 (m, 2H) 7.43 (d, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H)7.56 (d, J=8.22 Hz, 2H) 7.64 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98 (s,1H) 8.20 (d, J=1.76 Hz, 1H) 8.53 (d, J=2.35 Hz, 1H); MS (ESI, m/z):594.8 [M+H]⁺

Example 2152-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using intermediate 9, the title compound was obtained as described forthe example 214.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.51 (d, J=7.04 Hz, 3H) 1.64 (br dd,J=13.21, 6.75 Hz, 1H) 1.76-1.85 (m, 3H) 2.01-2.06 (m, 1H) 2.14 (s, 1H)2.15-2.20 (m, 1H) 2.84 (s, 3H) 3.82 (br d, J=6.46 Hz, 1H) 3.90 (s, 3H)3.98-4.02 (m, 1H) 4.42 (br dd, J=6.75, 3.23 Hz, 1H) 4.66 (s, 2H) 7.42(dd, J=8.22, 1.76 Hz, 4H) 7.54-7.59 (m, 4H) 7.86 (s, 1H) 7.98 (s, 1H)8.20 (d, J=2.35 Hz, 1H) 8.53 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 594.8 [M+H]⁺

Example 2162-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using intermediate 11, the title compound was obtained as described forthe example 214.

¹H NMR (600 MHz, CD₃OD) δ ppm 0.85-0.88 (m, 1H) 0.89-0.92 (m, 1H)0.99-1.01 (m, 1H) 1.01-1.04 (m, 1H) 1.64 (br dd, J=13.50, 6.46 Hz, 1H)1.75-1.88 (m, 3H) 2.01-2.07 (m, 1H) 2.16-2.24 (m, 2H) 2.79 (d, J=1.76Hz, 3H) 3.00 (br s, 2H) 3.15-3.21 (m, 2H) 3.34-3.43 (m, 4H) 3.90 (s, 3H)4.00 (dt, J=6.46, 4.11 Hz, 1H) 4.42 (td, J=7.34, 4.70 Hz, 1H) 4.66 (s,2H) 7.26 (d, J=8.31 Hz, 2H) 7.37-7.40 (m, 2H) 7.40-7.43 (m, 2H)7.49-7.52 (m, 1H) 7.86 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=1.76 Hz, 1H) 8.54(d, J=2.35 Hz, 1H);

MS (ESI, m/z): 606.3 [M+H]⁺

Example 2172-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using intermediate 12, the title compound was obtained as described forthe example 214.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.49 (s, 5H) 1.60-1.61 (m, 1H) 1.60-1.66(m, 1H) 1.80-1.88 (m, 3H) 2.02-2.08 (m, 1H) 2.17 (br s, 1H) 2.87 (s, 3H)3.90 (s, 3H) 4.02 (br s, 1H) 4.40-4.47 (m, 1H) 4.67 (s, 2H) 7.42 (d,J=8.22 Hz, 2H) 7.51-7.58 (m, 4H) 7.58-7.62 (m, 2H) 7.85 (d, J=0.78 Hz,1H) 7.98 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 608.2 [M+H]⁺

Example 2182-amino-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Scheme for the preparation of the Compound of Example 218;

To a mixture of compound 213 (20 mg, 0.03 mmol) and K₂CO₃ (14 mg, 0.1mmol) in 0.3 ml of methanol was added 2-bromothanol (4 μl, 0.05 mmol).The reaction mixture was stirred at room temperature for 3 hrs, Afterconcentration under vacuum, the crude product was purified by HPLC togive 10 mg of off-white solid

¹H NMR (600 MHz, CD₃OD) δ ppm 1.60-1.71 (m, 1H) 1.75 (d, J=7.04 Hz, 3H)1.76-1.85 (m, 3H) 2.00-2.09 (m, 1H) 2.14-2.23 (m, 1H) 3.33-3.44 (m, 2H)3.56-3.73 (m, 4H) 3.83-3.87 (m, 2H) 3.90 (s, 3H) 4.00 (dt, J=6.60, 4.33Hz, 1H) 4.38-4.45 (m, 2H) 4.64-4.70 (m, 2H) 7.43 (d, J=8.22 Hz, 2H) 7.54(d, J=8.22 Hz, 2H) 7.56-7.61 (m, 2H) 7.64-7.71 (m, 2H) 7.85 (s, 1H) 7.98(s, 1H) 8.20 (d, J=1.76 Hz, 1H) 8.53 (s, 1H);

MS (ESI, m/z): 624.8 [M+H]⁺

Example 2192-amino-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using intermediate 9, the title compound was obtained as described forthe example 213 and 218.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.58 (d, J=7.04 Hz, 3H) 1.64 (br dd,J=13.21, 6.75 Hz, 1H) 1.72-1.87 (m, 3H) 2.00-2.07 (m, 1H) 2.15-2.23 (m,1H) 2.99 (br s, 2H) 3.17-3.22 (m, 3H) 3.35-3.44 (m, 4H) 3.80-3.85 (m,3H) 3.90 (s, 3H) 3.96-4.03 (m, 2H) 4.42 (td, J=7.34, 4.11 Hz, 1H) 4.66(s, 2H) 7.42 (d, J=8.22 Hz, 2H) 7.46 (d, J=8.22 Hz, 2H) 7.55-7.57 (m,2H) 7.60 (d, J=8.22 Hz, 2H) 7.86 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=2.35Hz, 1H) 8.52 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 624.8 [M+H]⁺

Example 2202-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using intermediate 11, the title compound was obtained as described forthe example 213 and 218.

¹H NMR (600 MHz, CD₃OD) δ ppm 0.85-0.88 (m, 1H) 0.91-0.94 (m, 1H)1.00-1.03 (m, 1H) 1.05-1.07 (m, 1H) 1.64 (dd, J=13.21, 6.75 Hz, 1H)1.74-1.86 (m, 2H) 1.99-2.07 (m, 1H) 2.15-2.21 (m, 1H) 3.13-3.18 (m, 3H)3.76-3.81 (m, 2H) 3.90 (s, 3H) 3.97-4.04 (m, 1H) 4.39-4.45 (m, 1H)4.61-4.71 (m, 2H) 7.25-7.28 (m, 1H) 7.35-7.43 (m, 3H) 7.49-7.58 (m, 4H)7.85 (s, 1H) 7.98 (s, 1H) 8.19 (d, J=1.76 Hz, 1H) 8.53 (d, J=1.76 Hz,1H); MS (ESI, m/z): 636.5 [M+H]⁺

Example 2212-amino-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using intermediate 12, the title compound was obtained as described forthe example 213 and 218.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.35-1.44 (m, 6H) 1.60 (br dd, J=12.91,7.43 Hz, 1H) 1.73-1.89 (m, 3H) 2.03 (br dd, J=13.50, 6.46 Hz, 1H)2.11-2.21 (m, 1H) 2.48-2.62 (m, 9H) 3.67 (t, J=6.06 Hz, 2H) 3.86 (s, 3H)3.96 (dt, J=6.95, 4.55 Hz, 1H) 4.36-4.46 (m, 1H) 4.59-4.72 (m, 2H) 7.40(d, J=7.83 Hz, 2H) 7.43-7.49 (m, 2H) 7.53 (dd, J=12.72, 8.41 Hz, 4H)7.75 (s, 1H) 7.83 (s, 1H) 7.97 (d, J=2.35 Hz, 1H) 8.24 (d, J=1.96 Hz,1H);

MS (ESI, m/z): 624.8 [M+H]⁺

Example 2226-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 222:

Intermediate 14

Using 6-fluoropyridine-3-boronic acid, the title compound was obtainedas described for the intermediate 2.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.20 (dd, J=8.51, 2.64 Hz, 1H) 8.20 (td,J=8.22, 2.35 Hz, 1H) 8.27 (d, J=2.93 Hz, 1H) 8.45 (d, J=2.93 Hz, 1H)8.48 (d, J=2.35 Hz, 1H);

MS (ESI+) m/z 234.1 [M+H]⁺

Intermediate 15

Using intermediate 14, the title compound was obtained as described forthe intermediate 4.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.60 (br dd, J=13.30, 7.04 Hz, 1H)1.71-1.84 (m, 3H) 2.00 (br dd, J=13.30, 6.26 Hz, 1H) 2.10-2.21 (m, 1H)3.92 (dt, J=6.55, 4.35 Hz, 1H) 4.39 (td, J=7.34, 4.50 Hz, 1H) 4.58 (s,2H) 7.15 (dd, J=8.41, 2.54 Hz, 1H) 7.26 (d, J=8.22 Hz, 2H) 7.38-7.43 (m,2H) 8.08 (d, J=2.35 Hz, 1H) 8.12-8.21 (m, 1H) 8.35 (d, J=2.35 Hz, 1H)8.43 (d, J=2.35 Hz, 1H);

MS (ESI+) m/z 485.2/487.3 [M+H]⁺

Intermediate 16

Using intermediate 15, the title compound was obtained as described forthe intermediate 13.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.18 (s, 12H) 1.58 (br dd, J=13.21, 7.34Hz, 1H) 1.69-1.84 (m, 3H) 1.96-2.03 (m, 1H) 2.15 (br d, J=7.63 Hz, 1H)3.93 (br d, J=6.46 Hz, 1H) 4.39 (br d, J=4.70 Hz, 1H) 4.63 (s, 2H) 7.13(dd, J=8.51, 2.64 Hz, 1H) 7.32 (d, J=7.63 Hz, 2H) 7.49-7.57 (m, 1H) 7.64(d, J=7.63 Hz, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.10-8.18 (m, 1H) 8.33 (d,J=1.76 Hz, 1H) 8.41 (d, J=2.35 Hz, 1H);

MS (ESI+) m/z 533.3 [M+H]⁺

Intermediate 17

Using intermediate 16, the title compound was obtained as described forthe compound 213.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.61 (d, J=6.65 Hz, 3H) 1.64 (br s, 1H)1.77-1.86 (m, 3H) 2.02-2.08 (m, 1H) 2.16-2.22 (m, 1H) 3.02 (br s, 2H)3.13 (br s, 2H) 3.32-3.40 (m, 4H) 3.97-4.02 (m, 2H) 4.05 (br d, J=6.26Hz, 1H) 4.41-4.46 (m, 1H) 4.67 (d, J=3.91 Hz, 2H) 7.16 (br dd, J=8.41,2.54 Hz, 1H) 7.43 (br d, J=8.22 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.55 (d,J=7.83 Hz, 2H) 7.60 (d, J=7.83 Hz, 2H) 8.19 (td, J=8.02, 2.74 Hz, 1H)8.35 (d, J=2.35 Hz, 1H) 8.47 (br d, J=2.74 Hz, 1H) 8.52 (d, J=2.35 Hz,1H);

MS (ESI+) m/z 595.3 [M+H]⁺

Example 2226-amino-6′-fluoro-N-((1S,2S)-2-(4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 17, the title compound was obtained as described forthe example 214.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.57 (d, J=6.65 Hz, 3H) 1.63 (br dd,J=13.50, 6.85 Hz, 1H) 1.72-1.89 (m, 3H) 2.00-2.08 (m, 1H) 2.14-2.23 (m,1H) 2.87 (s, 3H) 3.90-3.97 (m, 1H) 3.97-4.05 (m, 1H) 4.40-4.47 (m, 1H)4.63-4.71 (m, 2H) 7.16 (dd, J=8.61, 2.74 Hz, 1H) 7.32-7.50 (m, 4H) 7.55(br d, J=8.22 Hz, 2H) 7.58 (br d, J=8.22 Hz, 2H) 8.19 (ddd, J=8.61,7.43, 2.74 Hz, 1H) 8.35 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.74 Hz, 1H) 8.56(d, J=2.35 Hz, 1H);

MS (ESI+) m/z 609.3 [M+H]⁺

Example 2236-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 10, the title compound was obtained as described forthe example 222.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.49 (d, J=7.04 Hz, 3H) 1.63 (br d, J=6.65Hz, 1H) 1.84 (br d, J=15.65 Hz, 3H) 2.06 (br s, 1H) 2.19 (br d, J=8.61Hz, 1H) 2.84 (s, 3H) 3.74 (br d, J=6.26 Hz, 1H) 4.00 (br s, 1H) 4.43 (brs, 1H) 4.67 (d, J=3.13 Hz, 2H) 7.15 (br dd, J=9.00, 2.74 Hz, 1H) 7.42(dd, J=7.83, 3.52 Hz, 4H) 7.54 (br dd, J=7.83, 5.09 Hz, 4H) 8.15-8.22(m, 1H) 8.35 (br d, J=2.35 Hz, 1H) 8.46 (s, 1H) 8.50 (br d, J=1.96 Hz,1H);

MS (ESI+) m/z 609.4 [M+H]⁺

Example 2246-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 11, the title compound was obtained as described forthe example 222.

¹H NMR (400 MHz, CD₃OD) δ ppm 0.91-0.95 (m, 2H) 1.01-1.06 (m, 2H) 1.64(br dd, J=13.21, 6.75 Hz, 1H) 1.76-1.85 (m, 3H) 2.01-2.06 (m, 1H) 2.14(s, 1H) 2.15-2.20 (m, 1H) 2.80 (s, 3H) 3.34 (s, 2H) 3.99 (br d, J=4.30Hz, 1H) 4.43 (br d, J=4.70 Hz, 1H) 4.67 (d, J=3.52 Hz, 2H) 7.12-7.16 (m,1H) 7.40 (dd, J=14.28, 8.41 Hz, 4H) 7.52 (br dd, J=8.22, 3.91 Hz, 4H)8.18 (s, 1H) 8.35 (d, J=2.35 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H) 8.45 (s,1H);

MS (ESI+) m/z 621.5 [M+H]⁺

Example 2256-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 12, the title compound was obtained as described forthe example 222.

MS (ESI+) m/z 623.3 [M+H]⁺

Example 2266-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 226:

Using intermediate 17, the title compound was obtained as described forthe example 218.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.68 (m, 4H) 1.77-1.87 (m, 3H)2.02-2.09 (m, 1H) 2.15-2.23 (m, 1H) 3.13 (br s, 2H) 3.17-3.26 (m, 2H)3.46 (br s, 4H) 3.77 (br s, 1H) 3.82-3.87 (m, 2H) 4.02 (br d, J=4.70 Hz,2H) 4.11 (br d, J=6.26 Hz, 1H) 4.44 (br dd, J=11.74, 7.43 Hz, 1H) 4.67(d, J=2.74 Hz, 2H) 7.17 (dd, J=8.61, 2.74 Hz, 1 H) 7.43 (d, J=8.22 Hz,2H) 7.49 (d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.62 (d, J=8.61 Hz,2H) 8.20 (td, J=8.02, 2.74 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.48 (br d,J=2.74 Hz, 1H) 8.57 (d, J=1.96 Hz, 1H);

MS (ESI+) m/z 639.4 [M+H]⁺

Example 2276-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 10, the title compound was obtained as described forthe example 226.

MS (ESI+) m/z 639.1 [M+H]⁺

Example 228 6-amino-6′-fluoro-N-alS,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 11, the title compound was obtained as described forthe example 226.

MS (ESI+) m/z 651.6 [M+H]⁺

Example 2296-amino-6′-fluoro-N-(1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)-piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 12, the title compound was obtained as described forthe example 226.

MS (ESI+) m/z 653.4 [M+H]⁺

Example 2306-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 230:

Intermediate 18

Using (1S,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine, the titlecompound was obtained as described for the intermediate 7.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.58-1.65 (m, 1H) 1.74-1.85 (m, 3H)2.01-2.08 (m, 1H) 2.12-2.18 (m, 1H) 2.60 (s, 3H) 3.41-3.48 (m, 1H) 3.92(q, J=5.87 Hz, 1H) 4.45-4.55 (m, 2H) 7.27 (d, J=8.22 Hz, 2H) 7.43-7.50(m, 3H) 7.65 (d, J=8.22 Hz, 1 H) 7.73 (d, J=8.22 Hz, 1H) 8.03 (d, J=8.22Hz, 1H);

MS (ESI+) m/z 310.1 [M+H]⁺

Intermediate 19

Using intermediate 18, the title compound was obtained as described forthe intermediate 4.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.45-1.54 (m, 1H) 1.71-1.82 (m, 2H)1.84-1.92 (m, 1H) 1.92-2.02 (m, 1H) 2.23-2.33 (m, 1H) 2.63 (s, 3H)3.81-3.91 (m, 1H) 4.29-4.44 (m, 1H) 4.63-4.75 (m, 2H) 5.90 (br d, J=6.46Hz, 1H) 6.35 (br s, 2H) 7.44 (d, J=8.22 Hz, 2H) 7.56-7.62 (m, 3H) 7.66(d, J=8.22 Hz, 2H) 8.01 (d, J=8.22 Hz, 2H) 8.15 (d, J=1.76 Hz, 1H); MS(ESI+) m/z 508.1/510.2 [M+H]⁺

Intermediate 20

To intermediate 19 (300 mg, 0.59 mmol) in 3 ml of THF was added1-methylpiperazine (0.13 ml, 1.18 mmol) followed by Ti(OiPr)₄ (0.7 ml,2.36 mmol). The mixture was stirred at 60° C. for 4 hr and then NaBH₃CN(0.11 g, 1.18 mmol) was added. The mixture was stirred for 1 h andextracted with EtOAc, washed with brine, dried over MgSO₄. Afterconcentration under vacuum, the crude product was purified by silicagelcolumn chromatography to give 200 mg of off-white solid.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.55-1.61 (m, 1H) 1.64 (d, J=7.04 Hz, 3H)1.72-1.84 (m, 3H) 1.97-2.05 (m, 1H) 2.09-2.17 (m, 1H) 2.88 (s, 3H) 3.11(br s, 2H) 3.36-3.49 (m, 4H) 3.95 (dt, J=6.75, 4.26 Hz, 1H) 4.14 (br d,J=6.46 Hz, 1H) 4.35 (td, J=7.34, 4.70 Hz, 1H) 4.61-4.68 (m, 2H) 7.42 (d,J=8.22 Hz, 2H) 7.50 (d, J=8.22 Hz, 2H) 7.57 (d, J=8.22 Hz, 2H) 7.65 (d,J=8.22 Hz, 2H) 8.13 (d, J=2.35 Hz, 1H) 8.20 (d, J=2.35 Hz, 1H);

MS (ESI+) m/z 592.2/594.3 [M+H]⁺

Example 2306-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 20 and 5-fluoropyridine-3-boronic acid, the titlecompound was obtained as described for the intermediate 14.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.54 (d, J=7.04 Hz, 3H) 1.63 (br dd,J=13.21, 6.75 Hz, 1H) 1.77-1.86 (m, 3H) 2.04 (br dd, J=12.91, 7.04 Hz,1H) 2.16-2.23 (m, 1H) 2.85 (s, 3H) 3.88 (br d, J=7.04 Hz, 1H) 3.97-4.03(m, 1H) 4.43 (br d, J=4.70 Hz, 1H) 4.64-4.70 (m, 2H) 7.42 (br dd,J=8.22, 4.11 Hz, 4H) 7.53 (br d, J=8.22 Hz, 2H) 7.56 (br d, J=8.22 Hz,2H) 7.96 (br d, J=9.39 Hz, 1H) 8.42 (s, 1H) 8.50 (d, J=2.35 Hz, 1H) 8.56(s, 1H) 8.70 (br s, 1H);

MS (ESI+) m/z 609.3 [M+H]⁺

Example 2312-amino-5-chloro-N-((1S,2S)-2-((4′-((1-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-5-chloronicotinic acid, the title compound was obtained asdescribed for the synthesis of intermediate 20.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.60 (dt, J=13.60, 7.09 Hz, 1H) 1.66 (d,J=6.65 Hz, 3H) 1.73-1.87 (m, 3H) 1.98-2.06 (m, 1H) 2.10-2.20 (m, 1H)2.90 (s, 2H) 3.15 (br s, 2H) 3.45 (br s, 4H) 3.96 (dt, J=6.65, 4.30 Hz,1H) 4.18 (q, J=6.65 Hz, 1H) 4.37 (td, J=7.24, 4.30 Hz, 1H) 4.61-4.71 (m,2H) 7.43 (m, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.59 (d, J=8.22 Hz,2H) 7.67 (m, J=8.22 Hz, 2H) 8.09 (d, J=2.74 Hz, 1H) 8.14 (d, J=2.74 Hz,1H);

MS (ESI+) m/z 548.3 [M+H]⁺

Example 2322-amino-5-fluoro-N-((1S,2S)-2-((4′41-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-5-fluoronicotinic acid, the title compound was obtained asdescribed for the synthesis of intermediate 20.

MS (ESI, m/z): 532.3 [M+H]⁺

Example 2332-amino-5-cyano-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-5-cyanonicotinic acid, the title compound was obtained asdescribed for the synthesis of intermediate 20.

MS (ESI, m/z): 539.3 [M+H]⁺

Example 2342-amino-6-chloro-N-((1S,2S)-2-((4′-((1-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-6-chloronicotinic acid, the title compound was obtained asdescribed for the synthesis of intermediate 20.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.56 (br dd, J=13.11, 7.24 Hz, 1H) 1.66(d, J=7.04 Hz, 3H) 1.70-1.85 (m, 3H) 2.01 (br dd, J=13.11, 6.46 Hz, 1H)2.07-2.19 (m, 2H) 2.90 (s, 3H) 3.09-3.21 (m, 2H) 3.39-3.58 (m, 4H)3.87-3.96 (m, 1H) 4.19 (br d, J=6.65 Hz, 1H) 4.35 (br d, J=4.70 Hz, 1H)4.57-4.73 (m, 2H) 6.56 (d, J=7.83 Hz, 1H) 7.42 (m, J=8.22 Hz, 2H) 7.52(d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.66 (m, J=8.22 Hz, 2H) 7.73(d, J=8.22 Hz, 1H);

MS (ESI, m/z): 548.3 [M+H]⁺

Example 2352-amino-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid, the title compound was obtained asdescribed for the synthesis of intermediate 20.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.58-1.64 (m, 1H) 1.66 (d, J=7.04 Hz, 3H)1.74-1.85 (m, 3H) 1.97-2.05 (m, 1H) 2.13-2.20 (m, 1H) 2.89 (s, 3H)3.02-3.27 (m, 4H) 3.46 (br s, 4H) 3.93-4.00 (m, 1H) 4.20 (q, J=6.46 Hz,1H) 4.35-4.42 (m, 1H) 4.65 (s, 2H) 6.95 (t, J=6.75 Hz, 1H) 7.43 (d,J=8.22 Hz, 2H) 7.52 (m, J=8.22 Hz, 2H) 7.58 (m, J=8.22 Hz, 2H) 7.67 (d,J=8.22 Hz, 2H) 7.99 (dd, J=6.46, 1.17 Hz, 1H) 8.33 (dd, J=7.34, 1.47 Hz,1H);

MS (ESI, m/z): 514.3 [M+H]⁺

Example 2366-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 236:

Intermediate 21

Using 1-(2-hydroxyethyl)piperazine, the title compound was obtained asdescribed for the intermediate 20.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.42 (d, J=6.46 Hz, 2H) 1.51-1.58 (m, 1H)1.71-1.81 (m, 3H) 1.97-2.04 (m, 1H) 2.08-2.15 (m, 1H) 2.61 (br s, 2H)3.47 (br d, J=5.28 Hz, 1H) 3.67 (t, J=5.87 Hz, 2H) 3.91 (dt, J=6.46,4.70 Hz, 1H) 4.35 (td, J=7.34, 4.70 Hz, 1H) 4.59-4.67 (m, 2H) 7.37 (brd, J=8.22 Hz, 2H) 7.39 (br d, J=8.22 Hz, 2H) 7.54 (d, J=7.63 Hz, 4H)7.90 (d, J=2.35 Hz, 1H) 8.05 (d, J=2.35 Hz, 1H);

MS (ESI+) m/z 622.2/624.2 [M+H]⁺

Example 2366-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using intermediate 21, the title compound was obtained as described forthe example 230.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.89, 6.85 Hz, 1H) 1.72(br d, J=6.65 Hz, 3H) 1.76-1.87 (m, 3H) 2.04 (br dd, J=12.72, 6.46 Hz,1H) 2.13-2.23 (m, 1H) 3.52-3.68 (m, 4H) 3.84 (br t, J=4.89 Hz, 2H) 4.00(br d, J=3.91 Hz, 1H) 4.35 (br d, J=6.65 Hz, 1H) 4.39-4.49 (m, 2H)4.61-4.73 (m, 2H) 7.43 (br d, J=7.83 Hz, 2H) 7.53 (br t, J=9.39 Hz, 4H)7.63 (br d, J=8.22 Hz, 2H) 7.98 (br d, J=9.78 Hz, 1H) 8.43 (s, 1H) 8.52(s, 1H) 8.61 (s, 1H) 8.71 (s, 1H);

MS (ESI+) m/z 639.3 [M+H]⁺

Example 2376-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using 6-fluoropyridine-3-boronic acid, the title compound was obtainedas described for the example 236.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.30, 6.65 Hz, 1H) 1.68(br d, J=7.04 Hz, 3H) 1.81 (br d, J=7.43 Hz, 3H) 1.98-2.08 (m, 1H)2.12-2.23 (m, 1H) 3.17-3.28 (m, 4H) 3.53 (br s, 4H) 3.84 (br d, J=4.30Hz, 2H) 3.99 (br s, 1H) 4.25 (br d, J=7.04 Hz, 1H) 4.42 (br d, J=4.70Hz, 1H) 4.62-4.72 (m, 2H) 7.16 (br d, J=7.83 Hz, 1H) 7.42 (br d, J=7.83Hz, 2H) 7.47-7.59 (m, 4H) 7.62 (br d, J=7.83 Hz, 2H) 8.19 (br t, J=8.02Hz, 1H) 8.34 (s, 1H) 8.47 (br s, 1H) 8.56 (s, 1H);

MS (ESI+) m/z 639.3 [M+H]⁺

Example 2386-amino-2′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using 2-fluoropyridine-3-boronic acid, the title compound was obtainedas described for the example 236.

MS (ESI+) m/z 639.3 [M+H]⁺

Example 2392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methylpiperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 239:

Intermediate 22

Using 4-(4-(1-trifluoroacetylpiperidino)methyl)phenylboronic acidpinacol ester, the title compound was obtained as described for theexample 134.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.39-1.48 (m, 2H) 1.63 (br dd, J=13.50,7.04 Hz, 1H) 1.76-1.86 (m, 4H) 1.86-1.95 (m, 3H) 2.04 (br dd, J=13.21,6.75 Hz, 1H) 2.18 (br dd, J=13.50, 5.87 Hz, 1H) 2.64 (br d, J=6.46 Hz,2H) 2.90-2.98 (m, 2H) 3.33 (s, 3H) 3.36 (br d, J=12.33 Hz, 3H) 3.89 (s,3H) 3.97-4.03 (m, 1H) 4.37-4.45 (m, 1H) 4.63-4.70 (m, 2H) 7.23 (br d,J=8.22 Hz, 2H) 7.40 (d, J=8.22 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.52 (d,J=8.22 Hz, 2H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (d, J=1.76 Hz, 1H) 8.51(d, J=2.35 Hz, 1H);

MS (ESI, m/z): 564.8 [M+H]⁺

Example 2392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((l-methylpiperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using intermediate 22 and formaldehyde, the title compound was obtainedas described for the example 214.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.42-1.54 (m, 2H) 1.63 (br dd, J=13.50,7.04 Hz, 1H) 1.75-1.88 (m, 4H) 1.92 (br d, J=14.67 Hz, 2H) 2.00-2.08 (m,1H) 2.17 (br dd, J=13.50, 5.87 Hz, 1H) 2.64 (br d, J=7.04 Hz, 2H) 2.82(s, 3H) 2.89-2.98 (m, 2H) 3.47 (br d, J=12.33 Hz, 2H) 3.89 (s, 3H)3.94-4.05 (m, 1H) 4.36-4.46 (m, 1H) 4.61-4.69 (m, 2H) 7.22 (d, J=8.22Hz, 2H) 7.39 (br d, J=8.22 Hz, 2H) 7.47 (br d, J=8.22 Hz, 2H) 7.51 (brd, J=8.22 Hz, 2H) 7.84 (s, 1H) 7.96 (s, 1H) 8.18 (d, J=1.76 Hz, 1H) 8.49(d, J=2.35 Hz, 1H);

MS (ESI, m/z): 579.8 [M+H]⁺

Example 2402-amino-N-((1S,2S)-2-((4′-((1-(2-hydroxyethyl)piperidin-4-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Scheme for the preparation of the Compound of Example 240:

To a mixture of intermediate 22 (30 mg, 0.05 mmol) and K₂CO₃ (22 mg,0.16 mmol) in 0.4 ml of DMF was added 2-bromoethanol (6 μl, 0.08 mmol).The mixture was stirred at room temperature for 4 hr and then water wasadded. The mixture was extracted with EtOAc, washed with brine, driedover MgSO₄. After concentration under vacuum, the crude residue waspurified by preparative HPLC to afford 27 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.26 (br d, J=13.50 Hz, 2H) 1.56-1.74 (m,4H) 1.74-1.89 (m, 4H) 2.04 (br dd, J=13.21, 6.16 Hz, 1H) 2.20 (br dd,J=13.50, 7.04 Hz, 1H) 2.64 (br d, J=7.04 Hz, 2H) 2.77 (br t, J=12.62 Hz,2H) 3.05-3.13 (m, 2H) 3.47 (br d, J=12.33 Hz, 2H) 3.75-3.81 (m, 2H) 3.92(s, 3H) 4.01-4.07 (m, 1H) 4.40-4.47 (m, 1H) 4.62-4.72 (m, 2H) 7.10 (brd, J=7.63 Hz, 1H) 7.20-7.26 (m, 3H) 7.27-7.33 (m, 2H) 7.41 (br d, J=7.63Hz, 2H) 7.87-7.90 (m, 1H) 7.88 (s, 1H) 8.03 (s, 1H) 8.23 (d, J=1.76 Hz,1H) 8.60 (br s, 1H);

MS (ESI, m/z): 609.8 [M+H]⁺

Example 241 methyl2-(4-((4′-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)-[1,1′-biphenyl]-4-yl)methyl)piperidin-1-yl)-acetate

Using intermediate 22 and methyl bromoacetate, the title compound wasobtained as described for the example 240.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.32 (br s, 2H) 1.61-1.71 (m, 4H)1.79-1.89 (m, 4H) 2.01-2.06 (m, 1H) 2.20 (br dd, J=13.79, 6.75 Hz, 1H)2.66 (br s, 2H) 2.85 (br s, 2H) 3.49 (br s, 2H) 3.79 (s, 3H) 3.92 (s,3H) 4.01 (br s, 2H) 4.02-4.06 (m, 1H) 4.44 (br dd, J=11.15, 7.04 Hz, 1H)4.63-4.73 (m, 2H) 7.11 (br d, J=7.63 Hz, 1H) 7.23-7.30 (m, 4H) 7.41 (brd, J=8.22 Hz, 2H) 7.88 (s, 1H) 8.02-8.04 (m, 1H) 8.23 (d, J=1.76 Hz, 1H)8.60 (s, 1H);

MS (ESI, m/z): 637.7 [M+H]⁺

Example 2422-amino-N-((1S,2S)-2-((4′-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using intermediate 22 and bromoacetamide, the title compound wasobtained as described for the example 240.

MS (ESI, m/z): 622.8 [M+H]⁺

Example 2432-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 243

Intermediate 23

A mixture of intermediate 4 (300 mg, 0.64 mmol), Pd(dba)₂ (7 mg, 0.01mmol), P(t-bu)₃ (8 mg, 0.04 mmol) in DMF (3 ml) was degassed withnitrogen and TEA (0.133 ml, 0.96 mmol), allyl alcohol (0.11 ml, 1.28mmol) were added. The mixture was heated at 100° C. for 1 h. Aftercooling, the mixture was partitioned between EA and water. The organiclayer was separated and washed with water, brine dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel with Et₂O-hexane mixtures as eluents togive 150 mg of off-white solid.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.75(br d, J=7.63 Hz, 1H) 1.79-1.85 (m, 2H) 1.94-2.04 (m, 3H) 2.16 (br d,J=6.46 Hz, 1H) 2.64 (br t, J=7.63 Hz, 2H) 2.89 (s, 3H) 3.02-3.07 (m, 2H)3.40 (br s, 2H) 3.46 (br s, 4H) 3.93 (s, 3H) 3.96-4.00 (m, 1H) 4.36-4.42(m, 1H) 4.54-4.65 (m, 3H) 7.16 (d, J=8.22 Hz, 2H) 7.27 (d, J=8.22 Hz,2H) 7.84-7.89 (m, 1H) 8.03 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.56 (d,J=2.35 Hz, 1H);

MS (ESI, m/z): 532.5 [M+H]⁺

Example 2432-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide

Using intermediate 23, the title compound was obtained as described forthe example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.75(br d, J=7.63 Hz, 1H) 1.79-1.85 (m, 2H) 1.94-2.04 (m, 3H) 2.16 (br d,J=6.46 Hz, 1H) 2.64 (br t, J=7.63 Hz, 2H) 2.89 (s, 3H) 3.02-3.07 (m, 2H)3.40 (br s, 2H) 3.46 (br s, 4H) 3.93 (s, 3H) 3.96-4.00 (m, 1H) 4.36-4.42(m, 1H) 4.54-4.65 (m, 3H) 7.16 (d, J=8.22 Hz, 2H) 7.27 (d, J=8.22 Hz,2H) 7.84-7.89 (m, 1H) 8.03 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.56 (d,J=2.35 Hz, 1H);

MS (ESI, m/z): 532.4 [M+H]⁺

Example 2442-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using intermediate 23 and dimethylamine (50% in THF), the title compoundwas obtained as described for the example 243.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.63-1.68 (m, 1H) 1.73-1.78 (m, 1H)1.80-1.83 (m, 3H) 1.96-2.05 (m, 3H) 2.17 (br d, J=6.46 Hz, 1H) 2.65 (brt, J=7.63 Hz, 2H) 2.84 (s, 6H) 3.06-3.14 (m, 2H) 3.94 (s, 3H) 3.98 (brs, 1H) 4.39 (br s, 1H) 4.55-4.67 (m, 3H) 7.18 (br d, J=7.63 Hz, 2H) 7.29(br d, J=7.63 Hz, 2H) 7.87-7.89 (m, 1H) 8.04 (s, 1H) 8.23 (d, J=1.76 Hz,1H) 8.57 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 477.5 [M+H]⁺

Example 2452-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 245

Intermediate 24

To a mixture of intermediate 4 (300 mg, 0.64 mmol) and(4-hydroxyphenyl)boronic acid (132 mg, 0.96 mmol) in 4 ml of1,4-dioxane/water (3/1) was added K₂CO₃ (264 mg, 1.91 mmol) followed byPd(PPh₃)₄ (37 mg, 0.03 mmol). The reaction mixture was heated at 100° C.for 3 hrs, cooled to room temperature, and extracted with EtOAc, driedover anhydrous MgSO₄ and concentrated under vacuum. After concentrationunder vacuum, the crude material was purified by flash chromatography onsilica gel with DCM-MeOH mixtures as eluents to give 250 mg of off-whitesolid.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.60 (br dd, J=13.21, 7.34 Hz, 1H)1.74-1.87 (m, 3H) 2.04 (br dd, J=12.62, 7.34 Hz, 1H) 2.10-2.20 (m, 1H)3.88 (s, 3H) 3.92-4.00 (m, 1H) 4.35-4.44 (m, 1H) 4.57 (d, J=12.33 Hz,1H) 4.66 (d, J=12.33 Hz, 2H) 6.78 (m, J=8.22 Hz, 2H) 7.33 (t, J=9.10 Hz,4H) 7.43 (m, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.91 (s, 1H) 8.15 (d, J=2.35Hz, 1H) 8.43 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 484.3 [M+H]⁺

Example 2452-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamide

A mixture of intermediate 24 (30 mg, 0.06 mmol) and K₂CO₃ (43 mg, 0.31mmol) was heated at 60° C. for 12 hrs, cooled to room temperature, andextracted with EtOAc, dried over anhydrous MgSO₄ and concentrated undervacuum. After concentration under vacuum, the crude residue was purifiedby preparative HPLC to afford 30 mg of the title compound

¹H NMR (400 MHz, CD₃OD) δ ppm 1.57-1.68 (m, 1H) 1.81 (br d, J=7.83 Hz,3H) 2.01 (br d, J=19.56 Hz, 1H) 2.16 (br d, J=12.91 Hz, 1H) 2.99 (s, 6H)3.61 (br s, 2H) 3.89 (s, 3H) 3.99 (br s, 1H) 4.37 (br d, J=3.52 Hz, 3H)4.64 (s, 2H) 7.05 (br d, J=8.22 Hz, 2H) 7.38 (br d, J=7.83 Hz, 2H) 7.50(br t, J=7.43 Hz, 3H) 7.84 (s, 1H) 7.96 (s, 1H) 8.19 (br s, 1H) 8.48 (s,1H);

MS (ESI, m/z): 555.4 [M+H]⁺

Example 2462-amino-N-((1S,2S)-2-((4′-(3-(dimethylamino)propoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamide

Using (3-chloropropyl)dimethylamine, title compound was obtained asdescribed for the example 245.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1H)1.73-1.86 (m, 3H) 2.04 (br dd, J=12.91, 7.63 Hz, 1H) 2.16 (br dd,J=13.21, 6.16 Hz, 1H) 2.19-2.28 (m, 2H) 2.94 (s, 6H) 3.32-3.41 (m, 2H)3.88 (s, 3H) 3.93-4.05 (m, 1H) 4.13 (t, J=5.87 Hz, 2H) 4.36-4.43 (m, 1H)4.58-4.68 (m, 2H) 6.97 (d, J=8.80 Hz, 2H) 7.37 (d, J=8.22 Hz, 2H) 7.46(t, J=8.51 Hz, 4H) 7.82 (s, 1H) 7.93 (s, 1H) 8.17 (d, J=2.35 Hz, 1H)8.43 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 569.4 [M+H]⁺

Example 2472-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methylpiperidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-bromo-1-methylpiperidine, title compound was obtained asdescribed for the example 245.

MS (ESI, m/z): 581.5 [M+H]⁺

Example 2482-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)prop-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 248

A mixture of intermediate 4 (40 mg, 0.09 mmol), Pd(dba)₂ (1 mg, 2 mol%), P(t-bu)₃ (1 mg, 6 mol %) in DMF (3 ml) was degassed with nitrogenand TEA (0.018 ml, 0.13 mmol), N,N-dimethylpropargylamine (0.016 ml,0.17 mmol) were added. The mixture was heated at 100° C. for 12 hrs.After cooling, the mixture was partitioned between EA and water. Theorganic layer was separated and washed with water, brine dried overMgSO₄ and concentrated in vacuo. After concentration under vacuum, thecrude residue was purified by preparative HPLC to afford 10 mg of thetitle compound.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (s, 2H) 1.78 (br dd, J=14.28, 6.85Hz, 2H) 1.99 (br dd, J=12.91, 6.65 Hz, 1H) 2.09-2.18 (m, 1H) 2.35 (s,3H) 3.12-3.18 (m, 1H) 3.32-3.34 (m, 4H) 3.42-3.50 (m, 2H) 3.58 (br d,J=7.04 Hz, 1H) 3.90 (s, 3H) 4.32-4.42 (m, 1H) 4.61 (s, 2H) 7.27-7.40 (m,4H) 7.76 (s, 1H) 7.87 (s, 1H) 7.98 (s, 1H) 8.24 (s, 1H);

MS (ESI, m/z): 473.4 [M+H]⁺

Example 2492-amino-N-((1S,2S)-2-((4-(4-hydroxybut-1-yn-1-yl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-butyn-1-ol, title compound was obtained as described for theexample 248.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1H)1.70-1.77 (m, 1H) 1.77-1.84 (m, 3H) 2.01 (br dd, J=12.62, 7.34 Hz, 1H)2.15 (br dd, J=13.21, 6.16 Hz, 1H) 2.57 (t, J=6.75 Hz, 2H) 3.69 (t,J=6.75 Hz, 2H) 3.94 (s, 3H) 4.32-4.40 (m, 1H) 4.54-4.63 (m, 2H)7.23-7.31 (m, 4H) 7.87 (s, 1H) 8.01 (s, 1H) 8.23 (d, J=2.35 Hz, 1H) 8.50(d, J=1.76 Hz, 1H); MS (ESI, m/z): 460.6 [M+H]⁺

Example 2502-amino-N-((1S,2S)-2-((4-(5-hydroxypent-1-yn-1-yl)-benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 4-pentyn-1-ol, title compound was obtained as described for theexample 248.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=12.91, 7.04 Hz, 1H)1.69-1.78 (m, 3H) 1.78-1.86 (m, 2H) 2.01 (br dd, J=12.91, 7.63 Hz, 1H)2.16 (br d, J=5.87 Hz, 1H) 2.45 (t, J=7.04 Hz, 2H) 3.66 (t, J=6.46 Hz,2H) 3.88-4.00 (m, 4H) 4.31-4.41 (m, 1H) 4.51-4.65 (m, 2H) 7.26 (s, 4H)7.87 (s, 1H) 8.01 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.51 (d, J=2.35 Hz,1H);

MS (ESI, m/z): 474.2 [M+H]⁺

Example 2512-amino-N-((1S,2S)-2-((4-(6-hydroxyhex-1-yn-1-yl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 5-hexyn-1-ol, title compound was obtained as described for theexample 248.

¹H NMR (600 MHz, CD₃OD) δ ppm 0.00-0.00 (m, 1H) 1.54-1.69 (m, 8H)1.72-1.78 (m, 1H) 1.78-1.86 (m, 3H) 1.91 (br d, J=7.63 Hz, 1H) 1.97-2.05(m, 1H) 2.12-2.20 (m, 1H) 2.24-2.30 (m, 2H) 2.32 (br d, J=3.52 Hz, 1H)2.40 (t, J=7.04 Hz, 1H) 2.45 (t, J=6.75 Hz, 1H) 2.43-2.43 (m, 1H) 3.55(t, J=6.46 Hz, 2H) 3.56-3.60 (m, 1H) 3.94 (d, J=1.17 Hz, 3H) 4.35-4.41(m, 2H) 4.43 (t, J=6.46 Hz, 1H) 4.54-4.65 (m, 2H) 4.68-4.68 (m, 1H)4.69-4.69 (m, 1H) 7.26 (d, J=7.04 Hz, 3H) 7.87 (s, 1H) 8.01 (s, 1H)8.19-8.26 (m, 1H) 8.48-8.53 (m, 1H);

MS (ESI, m/z): 488.3 [M+H]⁺

Example 2522-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)benzyl)oxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 252

To a mixture of compound 249 (30 mg, 0.07 mmol) and triethylamine (27μL, 0.2 mmol) in DCM (0.3 mL) was added methanesulfonyl chloride (12 μL,0.16 mmol). The mixture was stirred at room temperature for 2 hrs. Aftercompletion of conversion, the volatile was removed under reducedpressure. The crude residue was diluted with EtOH (0.3 mL) and1-methylpiperazine (16 μL, 0.13 mmol) was added. The mixture wasrefluxed for 2 hrs. After cooling, the crude residue was purified bypreparative HPLC to afford 20 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.21, 6.75 Hz, 1H) 1.75(br d, J=5.28 Hz, 1H) 1.80-1.84 (m, 2H) 1.98-2.02 (m, 1H) 2.16 (br dd,J=13.79, 6.75 Hz, 1H) 2.78 (br s, 2H) 2.89-2.93 (m, 3H) 3.44 (br s, 4H)3.55 (br s, 2H) 3.94 (s, 3H) 3.95-3.99 (m, 1H) 4.38 (br dd, J=11.15,7.04 Hz, 1H) 4.60 (s, 2H) 7.26-7.35 (m, 4H) 7.88 (s, 1H) 8.02 (s, 1H)8.23 (d, J=2.35 Hz, 1H) 8.55 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 542.5[M+H]⁺

Example 2532-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Scheme for the preparation of the Compound of Example 253:

Intermediate 25

To a mixture of intermediate 3 (300 mg, 1.38 mmol) and triethylamine(168 mg, 1.66 mmol) in 7 ml of DMF was added HATU (524 mg, 1.66 mmol)followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (263 mg, 1.38mmol). The mixture was stirred at room temperature for 1 hr and thensaturated sodium bicarbonate solution was added. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified through silicagelcolumn chromatography to give 326 mg of off-white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.47 (dt, J=13.99, 6.90 Hz, 1H) 1.72-1.82(m, 2H) 1.83-1.92 (m, 1H) 1.92-2.01 (m, 2H) 2.22-2.34 (m, 1H) 3.79-3.88(m, 1H) 4.32 (dd, J=7.04, 4.70 Hz, 1H) 4.56-4.68 (m, 2H) 5.81 (br d,J=6.65 Hz, 1H) 6.35 (br s, 2H) 7.26-7.38 (m, 4H) 7.53 (d, J=2.35 Hz, 1H)8.17 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 390.2/392.2 [M+H]⁺

Example 2532-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

To a mixture of intermediate 25 (40 mg, 0.1 mmol) and(4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester (51mg, 0.16 mmol) in 1 ml of 1,4-dioxane was added 0.15 ml of aq. 2N K₃PO₄followed by Pd(PPh₃)₄ (8 mg, 0.007 mmol). The reaction mixture washeated at 100° C. for 3 hrs, cooled to room temperature, and extractedwith EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum.The crude residue was purified by preparative HPLC to afford 23 mg ofthe title compound.

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.57 (br dd, J=13.30, 7.04 Hz, 1H)1.66-1.87 (m, 3H) 1.97 (dt, J=13.01, 6.60 Hz, 1H) 2.13 (br dd, J=13.11,6.85 Hz, 1H) 2.95 (s, 3H) 3.44-3.62 (m, 4H) 3.87-3.97 (m, 1H) 4.17 (s,2H) 4.31-4.39 (m, 1H) 4.60 (s, 2H) 6.25 (d, J=9.00 Hz, 1H) 7.21-7.35 (m,5H) 7.43 (d, J=8.22 Hz, 2H) 7.58 (d, J=8.61 Hz, 2H) 8.08 (d, J=9.00 Hz,1H);

MS (ESI, m/z): 500.3 [M+H]⁺

Example 2542-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester,the title compound was obtained as described for the example 201.

MS (ESI, m/z): 461.3 [M+H]⁺

Example 2552-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacolester, the title compound was obtained as described for the example 253.

MS (ESI, m/z): 475.3 [M+H]⁺

Example 2562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacolester, the title compound was obtained as described for the example 253.

MS (ESI, m/z): 489.3 [M+H]⁺

Example 2572-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acidpinacol ester, the title compound was obtained as described for theexample 253.

MS (ESI, m/z): 503.3 [M+H]⁺

Example 2582-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronicacid pinacol ester, the title compound was obtained as described for theexample 253.

MS (ESI, m/z): 544.3 [M+H]⁺

Example 2592-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-(benzyloxy)cyclopentan-1-amine and(1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 461.3 [M+H]⁺

Example 2602-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentan-1-amine and(1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 529.2 [M+H]⁺

Example 2612-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacolester, the title compound was obtained as described for the example 253.

MS (ESI, m/z): 422.2 [M+H]⁺

Example 2622-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acidpinacol ester, the title compound was obtained as described for theexample 253.

MS (ESI, m/z): 465.3 [M+H]⁺

Example 2632-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)boronicacid pinacol ester, the title compound was obtained as described for theexample 253.

MS (ESI, m/z): 505.3 [M+H]⁺

Example 2642-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)-nicotinamide

Using (4-cyanophenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

¹H NMR (400 MHz, CDCl₃) δ 1.59 (m, 2H) 1.85 (m, 4H) 2.10 (m, 2H) 2.24(m, 1H) 4.17 (br d, J=7.04 Hz, 1H) 4.28 (br d, J=7.04 Hz, 1H) 4.43-4.54(m, 1H) 4.56-4.67 (m, 2H) 7.13-7.19 (m, 1H) 7.13-7.19 (m, 1H) 7.13-7.19(m, 2H) 7.19-7.24 (m, 2H) 7.35 (br d, J=7.43 Hz, 2H) 7.64 (m, J=8.22 Hz,2H) 7.73 (m, J=8.22 Hz, 2H) 7.80 (s, 1H) 7.85-7.91 (m, 1H) 8.27 (s, 1H)8.58 (br s, 2H) 11.76-11.97 (m, 2H); MS (ESI, m/z): 413.2 [M+H]⁺

Example 2652-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)-nicotinamide

Using (3-cyanophenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

¹H NMR (400 MHz, CDCl₃) □□1.54-1.70 (m, 2H) 1.70-1.95 (m, 4H) 2.07 (brs, 2H) 2.23 (br s, 2H) 4.08 (br d, J=5.87 Hz, 1H) 4.33 (br s, 1H) 4.61(q, J=11.74 Hz, 2H) 7.14-7.20 (m, 1H) 7.20-7.29 (m, 2H) 7.29-7.38 (m,2H) 7.53-7.63 (m, 1H) 7.70 (br d, J=7.43 Hz, 1H) 7.75 (br d, J=7.43 Hz,1H) 7.87 (s, 1H) 7.91 (s, 1H) 8.26 (s, 1H) 8.87 (br s, 2H) 11.40-11.54(m, 1H);

MS (ESI, m/z): 413.2 [M+H]⁺

Example 2662-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)phenyl)nicotinamide

Using (4-(cyanomethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 253.

¹H NMR (400 MHz, CDCl₃) □□1.54-1.64 (m, 1H) 1.70 (br s, 1H) 1.83 (br s,2H) 1.97-2.05 (m, 2H) 3.11 (br s, 1H) 3.79 (s, 2H) 4.35 (br s, 1H) 4.64(s, 2H) 7.14 (br s, 1H) 7.18-7.24 (m, 3H) 7.39 (br t, J=7.83 Hz, 2H)7.55 (br d, J=7.83 Hz, 1H) 7.59 (s, 1H) 8.00 (br s, 1H) 8.34 (s, 1H)8.55-8.67 (m, 1H);

MS (ESI, m/z): 427.2 [M+H]⁺

Example 2672-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)nicotinamide

Using (4-phenoxyphenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

¹H NMR (400 MHz, CDCl₃) □1.23 (m, 2H) 1.56 (m, 2H) 1.75 (m, 4H) 2.07 (brs, 2H) 2.24 (br s, 2H) 4.12 (br d, J=5.87 Hz, 1H) 4.29 (br s, 1H)4.56-4.66 (m, 2H) 7.04 (br t, J=6.85 Hz, 3H) 7.17 (br d, J=7.43 Hz, 1H)7.22-7.26 (m, 4H) 7.30-7.39 (m, 3H) 7.39-7.44 (m, 2H) 7.50 (s, 1H) 7.74(s, 1H) 8.18 (s, 1H) 8.45 (br s, 2H) 11.28 (br s, 1H);

MS (ESI, m/z): 480.2 [M+H]⁺

Example 2682-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

Using (3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)boronic acid, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 2696-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-b]pyridinel-5-carboxamide

Using (6-(hydroxymethyl)pyridin-3-yl)boronic acid, the title compoundwas obtained as described for the example 253.

MS (ESI, m/z): 420.2 [M+H]⁺

Example 2702-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and(4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 514.3 [M+H]⁺

Example 2712-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-methylpiperazin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 2722-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and(4-(pyrrolidin-1-yl)piperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 582.3 [M+H]⁺

Example 2732-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 514.3 [M+H]⁺

Example 2742-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methylpiperazine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 532.3 [M+H]⁺

Example 2752-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and4-(pyrrolidin-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 568.4 [M+H]⁺

Example 2762-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and(4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 2772-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 582.3 [M+H]⁺

Example 2782-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine andN-(1-methylpiperidin-4-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 556.3 [M+H]⁺

Example 2792-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and2-(4-methylpiperazin-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 2802-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)-methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide

(1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(pyrrolidin-1-yl)piperidine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 586.4 [M+H]⁺

Example 2812-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and(4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 611.4 [M+H]⁺

Example 2822-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 500.3 [M+H]⁺

Example 2832-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((4-methylbenzyl)oxy)cyclopentan-1-amine and(4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 2842-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1 S,2 S)-2-((4-methylbenzyl)oxy)cyclopentan-1-amine and(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 582.3 [M+H]⁺

Example 2852-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(1,5-dimethyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 253.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 2862-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(1,3-dimethyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 253.

MS (ESI, m/z): 434.3 [M+H]⁺

Example 2872-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)boronic acid pinacolester, the title compound was obtained as described for the example 253.

MS (ESI, m/z): 495.2 [M+H]⁺

Example 2882-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)boronic acidpinacol ester, the title compound was obtained as described for theexample 253.

MS (ESI, m/z): 523.2 [M+H]⁺

Example 2892-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 2902-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-methylpiperazin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 556.3 [M+H]⁺

Example 2912-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 515.3 [M+H]⁺

Example 2922-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-((dimethyl-amino)methyl)phenyl)boronic acid, the title compound wasobtained as described for the example 253.

MS (ESI, m/z): 473.3 [M+H]⁺

Example 2932-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide

Using (1 S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethan-1-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 558.3 [M+H]⁺

Example 2946-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2′-methoxy-[3,3′-bipyridine]-5-carboxamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-methoxy-pyridin-3-yl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 447.2 [M+H]⁺

Example 2952-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-(dimethyl-amino)phenyl)boronic acid, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 459.3 [M+H]⁺

Example 2962-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-hydroxy-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 432.2 [M+H]⁺

Example 2972-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-amino-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 431.2 [M+H]⁺

Example 2982-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methylsulfonamido)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-(methyl-sulfonamido)phenyl)boronic acid, the title compound wasobtained as described for the example 253.

MS (ESI, m/z): 509.2 [M+H]⁺

Example 2992-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-(hydroxy-methyl)phenyl)boronic acid, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 446.2 [M+H]⁺

Example 3002-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-(amino-methyl)phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 445.3 [M+H]⁺

Example 3012-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxypropyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-(3-hydroxy-propyl)phenyl)boronic acid, the title compound wasobtained as described for the example 253.

MS (ESI, m/z): 474.3 [M+H]⁺

Example 3022-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(1r,4r)-4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)cyclohexan-1-ol,the title compound was obtained as described for the example 253

MS (ESI, m/z): 543.3 [M+H]⁺

Example 3032-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 3042-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(S)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 3053-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-5-hydroxybenzoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and3-borono-5-hydroxybenzoic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 476.2 [M+H]⁺

Example 3064-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-2-methylbenzoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and4-borono-2-methylbenzoic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 474.2 [M+H]⁺

Example 3072-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-amino-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 431.2 [M+H]⁺

Example 3083-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and3-boronobenzoic acid, the title compound was obtained as described forthe example 253.

MS (ESI, m/z): 460.2 [M+H]⁺

Example 3093-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)benzoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and3-amino-5-boronobenzoic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 475.2 [M+H]⁺

Example 3102-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 610.4 [M+H]⁺

Example 3112-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-methylpiperazin-1-yl)methanone, the titlecompound was obtained as described for the example 253.

MS (ESI, m/z): 556.3 [M+H]⁺

Example 3122-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 611.4 [M+H]⁺

Example 3132-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 446.2 [M+H]⁺

Example 3142-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formylphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-formyl-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 444.2 [M+H]⁺

Example 3154-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and4-boronobenzoic acid, the title compound was obtained as described forthe example 253.

MS (ESI, m/z): 460.2 [M+H]⁺

Example 3163-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)phenyl)propanoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and3-(4-boronophenyl)propanoic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 488.3 [M+H]⁺

Example 3172-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-hydroxyphenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 432.22 [M+H]⁺

Example 3182-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

Using (1S,2S)-2-(3,4-dimethylbenzyl)oxy)cyclopentan-1-amine andN-(1-methylpiperidin-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, the title compoundwas obtained as described for the example 253.

MS (ESI, m/z): 556.3 [M+H]⁺

Example 3192-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-(dimethyl-carbamoyl)phenyl)boronic acid, the title compound wasobtained as described for the example 253.

MS (ESI, m/z): 487.3 [M+H]⁺

Example 3202-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 3216-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-bipyridine]-5-carboxamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(6-(hydroxy-methyl)pyridin-3-yl)boronic acid, the title compound wasobtained as described for the example 253.

MS (ESI, m/z): 447.2 [M+H]⁺

Example 3222-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)benzoicacid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and2-amino-4-boronobenzoic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 475.2 [M+H]⁺

Example 3232-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamide

Using (1S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 476.3 [M+H]⁺

Example 3242-amino-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-fluoro-4-(hydroxymethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 253.

MS (ESI, m/z): 464.2 [M+H]⁺

Example 3252-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(pyrrolidin-1-yl)piperidine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 600.4 [M+H]⁺

Example 3262-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-(1-hydroxyethyl)phenyl)boronic acid, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 460.3 [M+H]⁺

Example 3272-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine andN,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 3282-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 529.3 [M+H]⁺

Example 3292-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(1-methylpiperidin-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanamine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 556.4 [M+H]⁺

Example 3302-amino-N-((1S,2S)-2-(3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 610.4 [M+H]⁺

Example 3312-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 611.4 [M+H]⁺

Example 3322-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and2-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 597.4 [M+H]⁺

Example 3332-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 460.3 [M+H]⁺

Example 3342-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-chloro-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 450 [M+H]⁺

Example 3352-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine andm-tolylboronic acid, the title compound was obtained as described forthe example 253.

MS (ESI, m/z): 430.2 [M+H]⁺

Example 3362-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3,5-dimethylphenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 444.3 [M+H]⁺

Example 3372-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-yl)morpholine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 584.4 [M+1-1]

Example 3382-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 3392-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 528.3 [M+H]⁺

Example 3402-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 514.3 [M+H]⁺

Example 3412-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 532.3 [M+H]⁺

Example 3422-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3,5-difluorophenyl)-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1 S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 550.3 [M+H]⁺

Example 3432-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine andN,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 3442-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-N,N-dimethylpyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 572.4 [M+H]⁺

Example 3452-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidin-3-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 501.3 [M+H]⁺

Example 3462-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-phenyl)-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1 S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(R)—N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 3472-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(S)—N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 542.3 [M+H]⁺

Example 3482-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 515.3 [M+H]⁺

Example 3492-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 515.3 [M+H]⁺

Example 3502-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 529.3 [M+H]⁺

Example 3512-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamide

Using (1 S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-hydroxy-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 432.2 [M+H]⁺

Example 3522-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(4-hydroxy-3-methoxyphenyl)boronic acid, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 462.23 [M+H]⁺

Example 3532-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3,4-dimethoxy-phenyl)boronic acid, the title compound was obtained asdescribed for the example 253.

MS (ESI, m/z): 476.3 [M+H]⁺

Example 3542-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and(3-(pyrrolidin-1-yl)phenyl)boronic acid pinacol ester, the titlecompound was obtained as described for the example 253

MS (ESI, m/z): 485.3 [M+H]⁺

Example 3552-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 435.2 [M+H]⁺

Example 3562-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and(4-(hydroxy-methyl)phenyl)boronic acid, the title compound was obtainedas described for the example 253.

MS (ESI, m/z): 460.3 [M+H]⁺

Example 3572-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2 S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine andN,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 556.4 [M+H]⁺

Example 3582-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol,the title compound was obtained as described for the example 253.

MS (ESI, m/z): 529.3 [M+H]⁺

Example 3592-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperazine,the title compound was obtained as described for the example 253.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.11 (t, J=7.63 Hz, 3H) 1.50 (s, 6H)1.58-1.67 (m, 1H) 1.70-1.88 (m, 3H) 1.98-2.06 (m, 1H) 2.10-2.17 (m, 1H)2.17 (s, 3H) 2.49-2.57 (q, J=7.63 Hz, 2H) 2.84 (br s, 4H) 3.24 (t,J=4.70 Hz, 4H) 3.91-4.00 (m, 1H) 4.40 (br d, J=4.70 Hz, 1H) 4.49-4.61(m, 2H) 6.98-7.05 (m, 2H) 7.09 (s, 1H) 7.64-7.80 (m, 4H) 8.31 (d, J=2.35Hz, 1H) 8.57 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 556.4 [M+H]⁺

Example 3602-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and2-(4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperazin-1-yl)ethan-1-ol,the title compound was obtained as described for the example 253.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.11 (t, J=7.43 Hz, 3H) 1.57 (s, 3H)1.61-1.64 (m, 1H) 1.64 (s, 3H) 1.69-1.89 (m, 3H) 2.01 (br dd, J=13.11,6.06 Hz, 1H) 2.10-2.29 (m, 4H) 2.53 (q, J=7.56 Hz, 2H) 2.88-3.13 (m, 4H)3.22-3.28 (m, 1H) 3.33-3.39 (m, 2H) 3.43 (br s, 2H) 3.83-3.90 (m, 1H)3.92-4.00 (m, 1H) 4.35-4.45 (m, 1H) 4.47-4.62 (m, 2H) 6.95-7.07 (m, 2H)7.09 (s, 1H) 7.65-7.84 (m, 4H) 8.29-8.36 (m, 1H) 8.56-8.64 (m, 1H);

MS (ESI, m/z): 600.3 [M+H]⁺

Example 3613-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-bromopyrazine-2-carboxamideand (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 462.3 [M+H]⁺

Example 362(S)-3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide

Using(S)-3-amino-6-bromo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamideand (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, thetitle compound was obtained as described for the example 253.

MS (ESI, m/z): 418.2 [M+H]⁺

Example 3632-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 363:

Intermediate 26

To a solution of trans-(1S,2S)-2-Aminocyclopentanol hydrochloride (8.0mmol) in DMF (5 ml) was added 1M potassium tert-butoxide in THF (20 ml)at room temperature. The mixture was allowed to stir for 30 min. Afterbeing allowed to stir for 30 min, 4-bromobenzyl bromide (9.6 mmol) wasadded to the mixture, and then allowed to stir for additional 2 h atroom temperature. The reaction mixture was then quenched with water andextracted with EtOAc. The separated organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The concentrated residue was used inthe next step without further purification.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.29-1.35 (m, 1H) 1.57-1.65 (m, 1H)1.65-1.77 (m, 2H) 1.96 (br dd, J=12.62, 6.75 Hz, 2H) 3.20-3.27 (m, 1H)3.51 (br d, J=5.28 Hz, 1H) 4.40-4.46 (m, 1H) 4.46-4.54 (m, 1H) 7.21 (brt, J=7.63 Hz, 2H) 7.40-7.48 (m, 2H); MS (ESI+) m/z 270 [M+H]⁺

Intermediate 27

To a solution of intermediate 26 (0.851 mmol) in 1,4-dioxane (4 ml) andwater (1 ml) was added1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(0.851 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0851 mmol) andpotassium carbonate (0.851 mmol). The mixture was heated to 100° C. andallowed to stir for overnight. After being cooled to room temperature,the reaction mixture was diluted with water (10 mL) and extracted withethyl acetate (10 mL). The separated organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The concentrated residue waspurified by flash column chromatography to afford the desired compound(265 mg, 0.7 mmol).

¹H NMR (600 MHz, CD₃OD) δ ppm 1.36-1.45 (m, 1H) 1.63-1.78 (m, 3H)1.97-2.07 (m, 2H) 2.26 (s, 3H) 2.30-2.71 (br s, 8H) 3.24 (td, J=7.48,4.99 Hz, 1H) 3.55 (s, 2H) 3.67-3.74 (m, 1H) 4.53 (d, J=11.74 Hz, 1H)4.60 (d, J=11.74 Hz, 1H) 7.38 (d, J=8.22 Hz, 2H) 7.42 (d, J=8.22 Hz, 2H)7.55-7.58 (m, 2H) 7.58-7.61 (m, 2H);

MS (ESI+) m/z 380 [M+H]⁺

Intermediate 28

To a solution of intermediate 27 (0.685 mmol) and2-amino-5-bromonicotinic acid (0.685 mmol) in N,N-dimethylformamide (5mL) was added diisopropylethylamine (3.425 mmol) and HATU (1.027 mmol)at room temperature. The reaction mixture was allowed to stir forovernight, concentrated in vacuo, diluted with EtOAc and washed withbrine. The separated organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The concentrated residue was purified by flashcolumn chromatography to afford the desired compound (0.653 mmol) as apale yellow oil.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.49-1.57 (m, 1H) 1.68-1.78 (m, 3H)1.95-2.01 (m, 1H) 2.07-2.13 (m, 1H) 2.41 (s, 3H) 2.49-2.79 (br s, 8H)3.56 (s, 2H) 3.91 (dt, J=6.90, 4.48 Hz, 1H) 4.34 (td, J=7.48, 4.40 Hz,1H) 4.57-4.65 (m, 2H) 7.35 (br d, J=8.22 Hz, 2H) 7.37 (br d, J=8.22 Hz,2H) 7.52 (d, J=7.63 Hz, 4H) 7.90 (d, J=2.35 Hz, 1H) 8.04 (d, J=2.35 Hz,1H);

MS (ESI+) m/z 579 [M+H]⁺

Example 3632-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To a solution of intermediate 28 (0.076 mmol) in 1,4-dioxane (4 ml) andwater (1 ml) was added (4-fluorophenyl)boronic acid (0.076 mmol),tetrakis(triphenylphosphine)-palladium(0) (0.0076 mmol) and potassiumcarbonate (0.076 mmol). The mixture was heated to 100° C. and allowed tostir for overnight. After being cooled to room temperature, the reactionmixture was diluted with water (10 mL) and extracted with ethyl acetate(10 mL). The separated organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The concentrated residue was purified bypreparative HPLC to afford the compound of Example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.23 (s, 1H), 7.64-7.47 (m, 8H),7.42 (d, 2H), 7.17 (t, 2H), 4.66 (qd, 2H), 4.45-4.39 (m, 1H), 4.25 (s,1H), 4.09-3.90 (m, 1H), 3.62 (s, 1H), 3.53 (br s, 2H), 3.39 (br s, 2H),2.94 (s, 3H), 2.19-2.12 (m, 1H), 2.05-1.97 (m, 1H), 1.83-1.75 (m, 3H),1.66-1.57 (m, 1H); MS (ESI+) m/z 594 [M+H]⁺

Example 3642-amino-5-(3,4-difluorophenyl)-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 3,4-difluorophenylboronic acid, the title compound was obtained asdescribed for the example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.26 (s, 1H), 7.71-7.52 (m, 8H),7.42-7.33 (m, 3H), 4.65 (qd, 2H), 4.41 (m, 1H), 4.32 (s, 2H), 3.98 (m,1H), 3.57 (br s, 2H), 3.48 (br s, 2H), 2.94 (s, 3H), 2.18-2.05 (m, 1H),2.04-1.99 (m, 1H), 1.81-1.73 (m, 3H), 1.66-1.59 (m, 1H);

MS (ESI+) m/z 612 [M+H]⁺

Example 3652-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide

Using 4-trifluoromethylphenylboronic acid, the title compound wasobtained as described for the example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.36 (s, 1H), 7.83 (d, J=8.0 Hz,2H), 7.75 (d, J=12.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.54-7.50 (m, 4H),7.42 (d, J=8.0 Hz, 2H), 4.69-4.62 (qd, 2H), 4.44-4.39 (m, 1H), 4.27 (s,2H), 4.02-4.00 (m, 1H), 3.54 (br s, 2H), 3.42 (br s, 2H), 2.94 (s, 3H),2.21-2.05 (m, 1H), 2.05-1.97 (m, 1H), 1.87-1.76 (m, 3H), 1.68-1.59 (m,1H);

MS (ESI+) m/z 644 [M+H]⁺

Example 3662-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using1-methyl-4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-piperidine,the title compound was obtained as described for the example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.92(s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.57-7.50 (m, 4H), 7.42 (d, J=8.0 Hz,2H), 4.66 (s, 2H), 4.59-4.53 (m, 1H), 4.43-4.38 (m, 1H), 4.25 (s, 2H),4.12-4.01 (m, 2H), 3.69-3.66 (d, 2H), 3.53 (br s, 2H), 3.39 (br s, 2H),3.25-3.20 (m, 1H), 2.93 (s, 3H), 2.92 (s, 3H), 2.41-2.33 (m, 4H),2.19-1.97 (m, 2H), 1.84-1.76 (m, 3H), 1.69-1.60 (m, 1H);

MS (ESI+) m/z 663 [M+H]⁺

Example 3672-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-nicotinamide

Using 4-(4-Methylpiperazin-1-yl)phenylboronic acid, the title compoundwas obtained as described for the example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 8.18 (s, 1H), 7.64-7.50 (m, 8H),7.43 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 4.66 (s, 2H), 4.43-4.39(m, 1H), 4.25 (s, 2H), 4.03-4.00 (m, 1H), 3.92 (d, J=1.2 Hz, 2H), 3.62(d, J=1.2 Hz, 2H), 3.52 (br s, 2H), 3.39 (br s, 2H), 3.26-3.20 (m, 2H),3.12-3.06 (m, 2H), 2.96 (s, 3H), 2.93 (s, 3H), 2.18-2.13 (m, 1H),2.05-1.92 (m, 1H), 1.83-1.76 (m, 3H), 1.66-1.59 (m, 1H);

MS (ESI+) m/z 674 [M+H]⁺

Example 3682-amino-N-((1S,2S)-2-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid, the titlecompound was obtained as described for the example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.66 (s, 1H), 8.29 (s, 1H), 7.73 (d, J=8.0 Hz,2H), 7.65-7.52 (m, 8H), 7.43 (d, J=8.0 Hz, 2H), 4.66 (s, 2H), 4.42 (m,1H), 4.31 (s, 2H), 4.21 (s, 2H), 4.02 (m, 1H), 3.53 (br, 8H), 3.46 (br,4H), 3.29 (br, 4H), 2.94 (s, 3H), 2.93 (s, 3H), 2.23-2.10 (m, 1H),2.04-1.98 (m, 1H), 1.88-1.75 (m, 3H), 1.67-1.60 (m, 1H);

MS (ESI+) m/z 688 [M+H]⁺

Example 3692-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-(Hydroxymethyl)phenylboronic acid, the title compound wasobtained as described for the example 363.

¹HNMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.26 (s, 1H), 7.70 (d, J=8.0 Hz,1H), 7.61-7.53 (m, 5H), 7.46-7.41 (m, 6H), 4.66 (s, 2H), 4.64 (s, 2H),4.42 (m, 1H), 3.99 (m, 1H), 3.91 (s, 2H), 3.35 (br s, 2H), 3.00 (br s,2H), 2.88 (s, 3H), 2.22-2.10 (m, 1H), 2.04 (m, 1H), 1.85-1.74 (m, 3H),1.63 (m, 1H); MS (ESI+) m/z 606 [M+H]⁺

Example 3702-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide

Using 3-tolylboronic acid, the title compound was obtained as describedfor the example 363.

¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.23 (s, 1H), 7.72-7.32 (m,11H), 7.24 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 4.41 (m, 1H), 4.06 (s, 2H),4.00 (m, 1H), 3.43 (br s, 2H), 3.17 (br s, 2H), 2.90 (s, 3H), 2.39 (s,3H), 2.18 (m, 1H), 2.04 (m, 1H), 1.89-1.75 (m, 3H), 1.65-1.60 (m, 1H);

MS (ESI+) m/z 590 [M+H]⁺

Example 3712-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide

Using phenylboronic acid, the title compound was obtained as describedfor the example 363.

MS (ESI+) m/z 576 [M+H]⁺

Example 3722-amino-5-(4-hydroxyphenyl)-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-hydroxyphenylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 592 [M+H]⁺

Example 3732-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-chloro-3-fluorophenylboronic acid, the title compound wasobtained as described for the example 363.

MS (ESI+) m/z 629 [M+H]⁺

Example 3742-amino-5-methyl-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using trimethylboroxine, the title compound was obtained as describedfor the example 363.

MS (ESI+) m/z 514 [M+H]⁺

Example 3756-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using 3-pyridylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 577 [M+H]⁺

Example 3762-amino-5-(4-methoxyphenyl)-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-methoxyphenylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 606 [M+H]⁺

Example 3776-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamide

Using 4-pyridylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 577 [M+H]⁺

Example 3782-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-nicotinamide

Using (4-((4-methylpiperidin-1-yl)methyl)phenyl)boronic acid, the titlecompound was obtained as described for the example 363.

MS (ESI+) m/z 687 [M+H]⁺

Example 3792-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide

Using (4-(morpholinomethyl)phenyl)boronic acid, the title compound wasobtained as described for the example 363.

MS (ESI+) m/z 675 [M+H]⁺

Example 3802-amino-N-((1S,2S)-2-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-(Tetrahydro-pyran-4-yl)-1H-pyrazole-4-boronic acid pinacolester, the title compound was obtained as described for the example 363.

MS (ESI+) m/z 650 [M+H]⁺

Example 3812-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamide

Using 4-morpholinophenylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 661 [M+H]⁺

Example 3822-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 1-cyclohexenylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 580 [M+H]⁺

Example 3832-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 3,4-dimethoxyphenylboronic acid, the title compound was obtainedas described for the example 363.

MS (ESI+) m/z 636 [M+H]⁺

Example 3846-amino-2′,6′-difluoro-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamide

Using 2,6-difluoropyridine-4-boronic acid, the title compound wasobtained as described for the example 363.

MS (ESI+) m/z 613 [M+H]⁺

Example 3852-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide

Using 4-Methyl-3-thienylboronic acid, the title compound was obtained asdescribed for the example 363.

MS (ESI+) m/z 596 [M+H]⁺

Example 3866-amino-6′-fluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide

Using 6-fluoro-3-pyridinylboronic acid, the title compound was obtainedas described for the example 363.

MS (ESI+) m/z 595 [M+H]⁺

Example 3872-amino-N-((1S,2S)-2-((4′-(4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)-nicotinamide

Using (1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)boronic acid, thetitle compound was obtained as described for the example 363.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=14.09, 7.04 Hz, 1H)1.75-1.88 (m, 3H) 2.04 (br dd, J=12.33, 7.63 Hz, 1H) 2.15-2.23 (m, 1H)2.87 (s, 3H) 2.90-3.06 (m, 4H) 3.33 (br s, 4H) 3.86 (s, 2H) 3.98-4.04(m, 1H) 4.39-4.44 (m, 1H) 4.62-4.69 (m, 2H) 6.75-6.98 (m, 1H) 7.39-7.45(m, 4H) 7.55 (br d, J=8.22 Hz, 2H) 7.57 (br d, J=8.22 Hz, 2H) 8.20 (s,1H) 8.33 (d, J=1.76 Hz, 1H) 8.58 (d, J=1.76 Hz, 1H) 8.60 (s, 1H);

MS (ESI+) m/z 666.3 [M+H]⁺

Example 3882-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 388:

Intermediate 29

To a mixture of intermediate 3 (420 mg, 1.94 mmol) and triethylamine(0.40 ml, 2.90 mmol) in 10 ml of DMF was added HATU (884 mg, 2.32 mmol)followed by tert-butyl (3S,4S)-3-amino-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidine-1-carboxylate (647mg, 1.94 mmol). The mixture was stirred at room temperature for 1 hr andthen saturated sodium bicarbonate solution was added. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified through silicagelcolumn chromatography to give 800 mg of off-white solid.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.14-1.22 (t, 3H) 1.41 (br s, 9H) 2.27 (s,3H) 2.55-2.64 (q, 2H) 3.37-3.66 (m, 4H) 3.78 (dd, J=12.03, 5.58 Hz, 1H)4.10 (br s, 1H) 4.50-4.79 (m, 2H) 6.74 (br s, 2H) 7.04-7.15 (m, 3H) 7.98(d, J=1.76 Hz, 1H) 8.43 (br s, 1H);

MS (ESI, m/z): 534.3 [M+H]⁺

Example 3882-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 29 (40 mg, 0.07 mmol) and1-methylpyrazole-4-boronic acid pinacol ester (23 mg, 0.11 mmol) in 0.4ml of 1,4-dioxane/water (3/1) was added K₂CO₃ (31 mg, 0.22 mmol)followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture washeated at 100° C. for 3 hrs, cooled to room temperature, and extractedwith EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum.The crude residue was dissolved with 0.5 ml of CH₂Cl₂/TFA (10/1) and themixture was stirred for 2 hrs. After concentration under vacuum, thecrude residue was purified by preparative HPLC to afford 23 mg of thetitle compound.

¹H NMR (600 MHz, CD₃OD) ppm 1.13 (t, J=7.34 Hz, 3H) 2.23 (s, 2H) 2.57(q, J=7.24 Hz, 2H) 2.91 (dd, J=12.03, 4.40 Hz, 1H) 2.97-3.04 (m, 1H)3.16-3.22 (m, 1H) 3.36-3.43 (m, 1H) 3.91 (s, 3H) 4.05-4.10 (m, 1H) 4.48(br s, 1H) 4.57 (d, J=11.74 Hz, 1H) 4.65 (d, J=11.74 Hz, 1H) 7.06 (s,2H) 7.12 (s, 1H) 7.76 (s, 1H) 7.89 (s, 1H) 8.02 (d, J=2.35 Hz, 1H) 8.26(d, J=2.35 Hz, 1H),

MS (ESI, m/z): 435.5 [M+H]⁺

Example 3892-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamide

Using 4-hydroxymethylphenylboronic acid, the title compound was obtainedas described for the example 388.

MS (ESI, m/z): 461.6 [M+H]⁺

Example 3902-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid, the titlecompound was obtained as described for the example 388.

MS (ESI, m/z): 543.4 [M+H]⁺

Example 3912-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using (4-carbamoylphenyl)boronic acid, the title compound was obtainedas described for the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H)2.19-2.19 (m, 1H) 2.60 (q, J=7.70 Hz, 2H) 3.33-3.35 (m, 1H) 3.43-3.64(m, 2H) 3.77 (br dd, J=12.72, 7.24 Hz, 1H) 4.36 (br s, 1H) 4.55-4.73 (m,3H) 7.10 (s, 2H) 7.17 (s, 1H) 7.78 (d, J=8.22 Hz, 2H) 7.99 (d, J=8.61Hz, 2H) 8.44 (d, J=2.35 Hz, 1H) 8.62 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 474.5 [M+H]⁺

Example 3922-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamide

Using m-tolylboronic acid, the title compound was obtained as describedfor the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.43 Hz, 3H) 2.25 (s, 3H) 2.41(s, 3H) 2.60 (q, J=7.56 Hz, 2H) 3.43-3.65 (m, 3H) 3.77 (dd, J=12.52,7.04 Hz, 1H) 4.35 (br d, J=4.30 Hz, 1H) 4.62-4.74 (m, 3H) 7.09 (s, 2H)7.16 (s, 1H) 7.25 (br d, J=7.43 Hz, 1H) 7.36 (t, J=7.63 Hz, 1H)7.42-7.51 (m, 2H) 8.31 (d, J=1.96 Hz, 1H) 8.65 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 445.3 [M+H]⁺

Example 3934-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoicacid

Using 4-carboxyphenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.43 Hz, 3H) 2.23 (s, 3H) 2.59(q, J=7.56 Hz, 2H) 3.34-3.51 (m, 2H) 3.52-3.67 (m, 1H) 3.76 (br d,J=7.43 Hz, 1H) 4.13 (br s, 1H) 4.57-4.69 (m, 3H) 7.02-7.10 (m, 2H) 7.14(s, 1H) 7.79 (br d, J=8.22 Hz, 2H) 8.13 (br d, J=8.22 Hz, 2H) 8.37-8.45(m, 1H) 8.73 (d, J=1.56 Hz, 1H); MS (ESI, m/z): 475.4 [M+H]⁺

Example 3942-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamide

Using phenylboronic acid, the title compound was obtained as describedfor the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61(q, J=7.43 Hz, 2H) 3.42-3.51 (m, 1H) 3.51-3.65 (m, 2H) 3.77 (dd,J=12.91, 7.04 Hz, 1H) 4.35 (br d, J=4.30 Hz, 1H) 4.57-4.76 (m, 3H)7.06-7.13 (m, 2H) 7.17 (s, 1H) 7.35-7.58 (m, 3H) 7.68 (d, J=7.04 Hz, 2H)8.33 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 431.5[M+H]⁺

Example 3956-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4′-bipyridine]-5-carboxamide

Using pyridine-4-boronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.63 Hz, 3H) 2.26 (s, 3H) 2.62(q, J=7.56 Hz, 2H) 3.47 (br d, J=12.52 Hz, 1H) 3.52-3.67 (m, 2H) 3.77(br dd, J=12.72, 6.85 Hz, 1H) 4.34 (br d, J=3.91 Hz, 1H) 4.61-4.78 (m,3H) 7.07-7.13 (m, 2H) 7.13-7.19 (m, 1H) 7.99 (dd, J=8.02, 5.67 Hz, 1H)8.56 (d, J=1.96 Hz, 1H) 8.68-8.82 (m, 3H) 9.14 (s, 1H);

MS (ESI, m/z): 432.3 [M+H]⁺

Example 3966-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3′-bipyridine]-5-carboxamide

Using pyridine-3-boronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.63 Hz, 3H) 2.26 (s, 3H) 2.62(q, J=7.56 Hz, 2H) 3.47 (br d, J=12.52 Hz, 1H) 3.52-3.67 (m, 2H) 3.77(br dd, J=12.72, 6.85 Hz, 1H) 4.34 (br d, J=3.91 Hz, 1H) 4.60-4.78 (m,3H) 7.07-7.13 (m, 2H) 7.17 (d, J=7.06 Hz, 1H) 7.18 (s, 1H) 7.99 (dd,J=8.02, 5.67 Hz, 1H) 8.56 (d, J=1.96 Hz, 1H) 8.67-8.83 (m, 3H) 9.14 (s,1H);

MS (ESI, m/z): 432.3 [M+H]⁺

Example 3972-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamide

Using potassium vinyltrifluoroborate, the title compound was obtained asdescribed for the example 388.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.43 Hz, 3H) 2.26 (s, 3H) 2.61(q, J=7.56 Hz, 2H) 3.44-3.65 (m, 3H) 3.76 (br dd, J=12.91, 7.04 Hz, 1H)4.33 (br d, J=3.91 Hz, 1H) 4.59-4.74 (m, 3H) 5.42 (d, J=10.96 Hz, 1H)5.94 (d, J=17.61 Hz, 1H) 6.66 (dd, J=17.80, 11.15 Hz, 1H) 7.10 (s, 2H)7.16 (s, 1H) 8.02-8.08 (m, 1H) 8.66 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 381.3 [M+H]⁺

Example 3982-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamide

Using 4-fluorophenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.60(q, J=7.63 Hz, 2H) 3.44-3.59 (m, 2H) 3.76 (dd, J=12.62, 7.34 Hz, 2H)4.25-4.38 (m, 1H) 4.61-4.71 (m, 3H) 7.03-7.12 (m, 2H) 7.14-7.24 (m, 3H)7.60-7.69 (m, 2H) 8.32 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS(ESI, m/z): 499.3 [M+H]⁺

Example 3992-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamide

Using 4-formylphenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.30 (t, J=7.63 Hz, 3H) 2.26 (br s, 3H)2.58 (q, J=7.63 Hz, 2H), 3.43-3.49 (m, 1H) 3.50-3.65 (m, 2H) 3.77 (dd,J=12.62, 6.75 Hz, 1H), 4.17 (br s, 1H) 4.64 (br s, 2H) 4.77 (br s, 1H)6.59 (br s, 2H) 7.05-7.20 (m, 3H) 7.55-7.73 (m, 2H) 7.86 (br d, J=5.28Hz, 2H) 8.04 (br s, 1H) 8.46 (br s, 1H) 9.86 (br s, 1H);

MS (ESI, m/z): 459.5 [M+H]⁺

Example 4002-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-cyanophenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.34 Hz, 3H) 2.25 (s, 3H) 2.60(q, J=7.63 Hz, 2H) 3.43-3.49 (m, 1H) 3.50-3.65 (m, 2H) 3.77 (dd,J=12.62, 6.75 Hz, 1H) 4.35 (br d, J=4.11 Hz, 1H) 4.62-4.74 (m, 3H)7.04-7.14 (m, 2H) 7.16 (s, 1H) 7.78-7.84 (m, 2H) 7.84-7.88 (m, 2H)8.39-8.52 (m, 1H) 8.59 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 456.3 [M+H]⁺

Example 4012-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamide

Using 4-methylsulfonylphenylboronic acid, the title compound wasobtained as described for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.34 Hz, 3H) 2.25 (s, 3H) 2.60(q, J=7.63 Hz, 2H) 2.98 (s, 3H) 3.43-3.49 (m, 1H) 3.50-3.65 (m, 2H) 3.76(dd, J=12.62, 7.34 Hz, 1H) 4.33-4.38 (m, 1H) 4.62-4.71 (m, 3H) 7.05-7.13(m, 2H) 7.16 (s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H)8.32 (d, J=1.76 Hz, 1H) 8.59 (d, J=1.76 Hz, 1H);

MS (ESI, m/z):524.6 [M+H]⁺

Example 4022-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamide

Using 4-phenoxyphenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H)2.56-2.65 (m, 2H) 3.46 (br d, J=12.33 Hz, 1H) 3.52-3.61 (m, 2H) 3.76 (s,1H) 4.32-4.40 (m, 1H) 4.62-4.73 (m, 3H) 7.02 (d, J=7.63 Hz, 2H)7.04-7.12 (m, 4H) 7.13-7.19 (m, 2H) 7.38 (t, J=7.92 Hz, 2H) 7.66 (d,J=8.80 Hz, 2H) 8.29-8.34 (m, 1H) 8.68 (d, J=1.76 Hz, 1H); MS (ESI,m/z):523.7 [M+H]⁺

Example 4035-([1,1′-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-biphenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.60(q, J=7.63 Hz, 2H) 3.47 (br d, J=12.91 Hz, 1H) 3.51-3.62 (m, 2H) 3.77(dd, J=12.33, 7.04 Hz, 1H) 4.31-4.40 (m, 1H) 4.63-4.73 (m, 3H) 7.05-7.14(m, 2H) 7.17 (s, 1H) 7.34 (s, 1H) 7.36 (br d, J=7.63 Hz, 1H) 7.45 (t,J=7.63 Hz, 2H) 7.64 (d, J=7.63 Hz, 2H) 7.70-7.79 (m, 3H) 8.40 (d, J=1.76Hz, 1H) 8.64 (d, J=2.35 Hz, 1H);

MS (ESI, m/z):507.4 [M+H]⁺

Example 4042-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-benzyloxyphenylboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.24 (s, 3H) 2.60(q, J=7.63 Hz, 2H) 3.46 (br d, J=12.91 Hz, 1H) 3.49-3.60 (m, 2H) 3.76(dd, J=12.91, 7.04 Hz, 1H) 4.28-4.36 (m, 1H) 4.60-4.73 (m, 3H) 5.13 (s,2H) 7.03-7.13 (m, 4H) 7.16 (s, 1H) 7.23-7.32 (m, 1H) 7.36 (t, J=7.63 Hz,2H) 7.43 (d, J=7.04 Hz, 2H) 7.59 (d, J=8.80 Hz, 2H) 8.23-8.29 (m, 1H)8.60 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 537.8 [M+H]⁺

Example 4052-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-dimethylaminophenylboronic acid, the title compound was obtainedas described for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.60(q, J=7.24 Hz, 2H) 3.07 (s, 6H) 3.47 (br d, J=12.91 Hz, 1H) 3.57 (ddd,J=18.78, 12.91, 3.52 Hz, 2H) 3.76 (br dd, J=12.91, 7.04 Hz, 1H)4.32-4.37 (m, 1H) 4.61-4.72 (m, 3H) 7.02-7.12 (m, 4H) 7.16 (s, 1H) 7.62(d, J=8.80 Hz, 2H) 8.26 (d, J=1.76 Hz, 1H) 8.69 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 474.4 [M+H]⁺

Example 4062-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamide

Using quinoline-3-boronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.17 (t, J=7.34 Hz, 3H) 2.25 (s, 3H) 2.61(q, J=7.24 Hz, 2H) 3.48 (br d, J=12.91 Hz, 1H) 3.57-3.69 (m, 2H) 3.78(br dd, J=12.91, 7.04 Hz, 1H) 4.34-4.42 (m, 1H) 4.61-4.75 (m, 3H)7.05-7.15 (m, 2H) 7.18 (s, 1H) 7.78-7.93 (m, 1H) 7.93-8.09 (m, 1H) 8.18(br dd, J=8.22, 3.52 Hz, 2H) 8.63 (d, J=1.76 Hz, 1H) 8.86 (d, J=2.35 Hz,1H) 8.99-9.07 (m, 1H) 9.37 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 482.6 [M+H]⁺

Example 4072-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using benzo[b]furan-2-boronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61(q, J=7.63 Hz, 2H) 3.48 (br d, J=12.33 Hz, 1H) 3.53 (br dd, J=12.91,2.93 Hz, 1H) 3.60 (br dd, J=12.91, 4.70 Hz, 1H) 3.78 (br dd, J=12.62,7.34 Hz, 1H) 4.37 (br s, 1H) 4.63-4.72 (m, 3H) 7.04-7.14 (m, 2H)7.15-7.20 (m, 2H) 7.20-7.26 (m, 1H) 7.29 (br t, J=7.63 Hz, 1H) 7.51 (d,J=8.22 Hz, 1H) 7.58 (br d, J=7.63 Hz, 1H) 8.57 (d, J=1.76 Hz, 1H) 8.60(d, J=1.76 Hz, 1H);

MS (ESI, m/z): 471.5 [M+H]⁺

Example 4082-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamide

Using 2-naphthyleneboronic acid, the title compound was obtained asdescribed for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.24 (s, 3H) 2.60(q, J=7.43 Hz, 2H) 3.48 (br d, J=12.91 Hz, 1H) 3.53-3.69 (m, 2H) 3.78(dd, J=12.91, 7.04 Hz, 1H) 4.31-4.46 (m, 1H) 4.55-4.72 (m, 3H) 7.05-7.14(m, 2H) 7.17 (s, 1H) 7.47-7.58 (m, 2H) 7.79 (dd, J=8.22, 1.76 Hz, 1H)7.85-8.02 (m, 3H) 8.16 (s, 1H) 8.47 (d, J=1.76 Hz, 1H) 8.78 (d, J=1.76Hz, 1H); MS (ESI, m/z): 481.4 [M+H]⁺

Example 4092-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide

Using 4-trifluoromethylbenzeneboronic acid, the title compound wasobtained as described for the example 388

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61(q, J=7.24 Hz, 2H) 3.45 (br d, J=12.32 Hz, 1H) 3.49-3.62 (m, 2H) 3.75(dd, J=12.62, 6.75 Hz, 1H) 4.26-4.38 (m, 1H) 4.61-4.72 (m, 3H) 7.03-7.13(m, 2H) 7.16 (s, 1H) 7.33 (td, J=10.12, 6.75 Hz, 2H) 7.53-7.69 (m, 2H)8.29 (s, 1H) 8.48 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 499.6 [M+H]⁺

Example 4102-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamide

Using 2,4,5-trifluorophenylboronic acid, the title compound was obtainedas described for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61(q, J=7.24 Hz, 2H) 3.45 (br d, J=12.32 Hz, 1H) 3.49-3.62 (m, 2H) 3.75(dd, J=12.62, 6.75 Hz, 1H) 4.26-4.38 (m, 1H) 4.61-4.72 (m, 3H) 7.03-7.13(m, 2H) 7.16 (s, 1H) 7.33 (td, J=10.12, 6.75 Hz, 1H) 7.53-7.63 (m, 1H)8.29 (s, 1H) 8.48 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 485.3 [M+H]⁺

Example 4112-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-cyanomethylphenylboronic acid, the title compound was obtainedas described for the example 388.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (td, J=7.63, 2.35 Hz, 3H) 2.24 (d,J=4.11 Hz, 3H) 2.59 (qd, J=7.53, 3.23 Hz, 2H) 3.45-3.56 (m, 1H)3.67-3.74 (m, 1H) 3.77-3.88 (m, 1H) 3.93 (s, 2H) 3.98 (br dd, J=11.44,6.16 Hz, 1H) 4.11-4.28 (m, 1H) 4.58-4.70 (m, 3H) 7.07 (s, 2H) 7.14 (s,1H) 7.86 (d, J=2.93 Hz, 1H) 8.02 (s, 1H) 8.19 (d, J=11.15 Hz, 1H) 8.24(d, J=1.76 Hz, 1H) 8.59 (dd, J=7.04, 2.35 Hz, 1H);

MS (ESI, m/z): 470.8 [M+H]⁺

Example 4122-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-(4-N-Boc-piperidine)pyrazole-4-boronic acid, the title compoundwas obtained as described for the example 388 and following deprotectionwith TFA.

MS (ESI, m/z): 504.3 [M+H]⁺

Example 4132-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-(4-N-methylpiperidine)pyrazole-4-boronic acid, the titlecompound was obtained as described for the example 388.

MS (ESI, m/z): 518.3 [M+H]⁺

Example 4142-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-(benzyloxy)pyrrolidine-1-carboxylate, the title compoundwas obtained as described for the example 388.

MS (ESI, m/z): 393.2 [M+H]⁺

Example 4152-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-((4-methylbenzyl)oxy)pyrrolidine-1-carboxylate, the titlecompound was obtained as described for the example 388.

MS (ESI, m/z): 407.2 [M+H]⁺

Example 4162-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-((3-ethylbenzyl)oxy)pyrrolidine-1-carboxylate, the titlecompound was obtained as described for the example 388.

MS (ESI, m/z): 421.2 [M+H]⁺

Example 4172-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl(3S,4S)-3-amino-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidine-1-carboxylate,the title compound was obtained as described for the example 388.

MS (ESI, m/z): 439.2 [M+H]⁺

Example 4182-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl(3S,4S)-3-amino-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidine-1-carboxylate,the title compound was obtained as described for the example 388.

MS (ESI, m/z): 455.2 [M+H]⁺

Example 4192-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

Scheme for the preparation of the Compound of Example 419:

Intermediate 30

To a mixture of intermediate 29 (400 mg, 0.7 mmol) and4-carboxyphenylboronic acid (230 mg, 1.10 mmol) in 4 ml of1,4-dioxane/water (3/1) was added K₂CO₃ (310 mg, 2.2 mmol) followed byPd(PPh₃)₄ (40 mg, 0.03 mmol). The reaction mixture was heated at 100° C.for 3 hrs, cooled to room temperature, and extracted with EtOAc, driedover anhydrous MgSO₄ and concentrated under vacuum. The crude productwas purified through silicagel column chromatography to give 350 mg ofoff-white solid ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.43 Hz, 3H)1.46 (br d, J=1.96 Hz, 9H) 2.23 (s, 3H) 2.59 (q, J=7.56 Hz, 2H)3.40-3.51 (m, 2H) 3.52-3.65 (m, 1H) 3.76 (br d, J=7.43 Hz, 1H) 4.13 (brs, 1H) 4.57-4.74 (m, 3H) 7.06 (s, 2H) 7.14 (s, 1H) 7.79 (br d, J=8.22Hz, 2H) 8.13 (br d, J=8.22 Hz, 2H) 8.37-8.45 (m, 1H) 8.73 (d, J=1.56 Hz,1H);

MS (ESI, m/z): 575.3 [M+H]⁺

Example 4192-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

To a mixture of intermediate 30 (12 mg, 0.02 mmol) and triethylamine(0.04 ml, 0.03 mmol) in 0.2 ml of DMF was added HATU (10 mg, 0.03 mmol)followed by 4-amino-1-methylpiperidine (0.03 ml, 0.02 mmol). The mixturewas stirred at room temperature for 1 hr and then saturated sodiumbicarbonate solution was added. The mixture was extracted with EtOAc,washed with brine, dried over MgSO₄, and concentrated in vacuo. Thecrude residue was dissolved with 0.5 ml of CH₂Cl₂/TFA (10/1) and themixture was stirred for 2 hrs. After concentration under vacuum, thecrude residue was purified by preparative HPLC to afford 10 mg of thetitle compound.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 1.86-1.98 (m, 2H)2.23 (br s, 3H) 2.25 (s, 3H) 2.61 (q, J=7.70 Hz, 2H) 2.89 (s, 3H)3.10-3.26 (m, 2H) 3.47 (br d, J=12.52 Hz, 1H) 3.52-3.66 (m, 3H) 3.77(dd, J=12.72, 6.85 Hz, 1H) 4.11-4.23 (m, 1H) 4.32-4.43 (m, 1H) 4.53-4.77(m, 3H) 7.05-7.14 (m, 2H) 7.17 (s, 1H) 7.81 (d, J=8.22 Hz, 2H) 7.88-7.99(m, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.74 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 571.4 [M+H]⁺

Example 4202-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide

Using 4-methylcyclohexylamine, the title compound was obtained asdescribed for the example 419.

¹H NMR (600 MHz, CD₃OD) δ ppm 0.93 (d, J=6.46 Hz, 1H) 1.00 (d, J=6.46Hz, 2H) 1.09 (br d, J=14.09 Hz, 1H) 1.16 (t, J=7.63 Hz, 3H) 1.38-1.48(m, 2H) 1.59-1.73 (m, 3H) 1.75-1.84 (m, 2H) 1.96 (br d, J=11.15 Hz, 1H)2.25 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 3.32-3.36 (m, 1H) 3.47 (br d,J=12.91 Hz, 1H) 3.51-3.61 (m, 2H) 3.76 (dd, J=12.91, 7.04 Hz, 2H) 3.99(br s, 1H) 4.35 (br s, 1H) 4.62-4.72 (m, 3H) 7.03-7.14 (m, 2H) 7.16 (s,1H) 7.76 (dd, J=8.51, 4.40 Hz, 2H) 7.91 (dd, J=8.22, 2.35 Hz, 2H) 8.42(d, J=2.35 Hz, 1H) 8.58-8.62 (m, 1H);

MS (ESI, m/z): 570.5 [M+H]⁺

Example 4212-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonyl)phenyl)nicotinamide

Using 4-methylpiperidine, the title compound was obtained as describedfor the example 419.

¹H NMR (600 MHz, CD₃OD) δ ppm 0.98 (d, J=6.46 Hz, 3H) 1.09-1.22 (m, 3H)1.16 (t, J=7.63, 3H) 1.62 (br d, J=11.74 Hz, 1H) 1.66-1.74 (m, 2H) 1.79(br d, J=12.91 Hz, 1H) 2.23 (s, 3H) 2.53-2.63 (q, J=7.63 Hz, 2H) 2.85(br t, J=12.33 Hz, 1H) 3.11 (br t, J=12.33 Hz, 1H) 3.39-3.49 (m, 2H)3.55-3.61 (m, 1H) 3.68 (br d, J=12.91 Hz, 1H) 3.75 (td, J=11.74, 7.04Hz, 1H) 4.12 (br s, 1H) 4.58-4.64 (m, 3H) 7.02-7.11 (m, 2H) 7.13 (s, 1H)7.51 (d, J=8.22 Hz, 2H) 7.76 (d, J=8.22 Hz, 2H) 8.36 (d, J=1.76 Hz, 1H)8.70 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 556.5 [M+H]⁺

Example 4222-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using dimethylamine, the title compound was obtained as described forthe example 419.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.15 (t, J=7.63 Hz, 3H) 2.22 (s, 3H) 2.58(q, J=7.63 Hz, 2H) 3.01 (s, 3H) 3.11 (s, 3H) 3.38-3.50 (m, 2H) 3.52-3.66(m, 1H) 3.67-3.81 (m, 1H) 4.12 (br s, 1H) 4.57-4.68 (m, 3H) 7.05 (s, 2H)7.13 (s, 1H) 7.54 (d, J=8.80 Hz, 2H) 7.75 (d, J=8.22 Hz, 2H) 8.36 (d,J=1.76 Hz, 1H) 8.68 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 502.4 [M+H]⁺

Example 4232-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide

Scheme for the preparation of the Compound of Example 423:

Intermediate 31

Using intermediate 29 and 4-formylphenylboronic acid, the title compoundwas obtained as described for the synthesis of intermediate 30.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.30 (t, J=7.63 Hz, 3H), 1.42 (s, 9H),2.26 (br s, 3H) 2.58 (q, J=7.63 Hz, 2H) 3.37-3.84 (m, 4H) 4.17 (br s,1H) 4.64 (br s, 2H) 4.77 (br s, 1H) 6.59 (br s, 2H) 7.05-7.20 (m, 3H)7.55-7.73 (m, 2H) 7.86 (br d, J=5.28 Hz, 2H) 8.04 (br s, 1H) 8.46 (br s,1H) 9.86 (br s, 1H); MS (ESI, m/z): 559.4 [M+H]⁺

Example 4232-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide

To a mixture of intermediate 31 (40 mg, 0.07 mmol) in 0.4 ml ofdichloroethane was added 4-methylpiperidine (0.017 ml, 0.14 mmol)followed by NaBH(OAc)₃ (30 mg, 0.21 mmol). The mixture was stirred atroom temperature for 4 hr and then water was added. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude residue was dissolved with 0.5 ml ofCH₂Cl₂/TFA (10/1) and the mixture was stirred for 2 hrs. Afterconcentration under vacuum, the crude residue was purified bypreparative HPLC to afford 10 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 0.99 (d, J=6.46 Hz, 3H) 1.16 (t, J=7.34Hz, 3H) 1.34-1.46 (m, 2H) 1.91 (br d, J=14.09 Hz, 2H) 2.25 (s, 3H) 2.61(q, J=7.63 Hz, 2H) 2.93-3.07 (m, 2H) 3.43-3.49 (m, 3H) 3.57 (ddd,J=16.43, 12.91, 3.52 Hz, 2H) 3.76 (dd, J=12.62, 6.75 Hz, 2H) 4.27-4.39(m, 3H) 4.59-4.76 (m, 3H) 7.05-7.14 (m, 2H) 7.17 (s, 1H) 7.60 (d, J=8.22Hz, 2H) 7.80 (d, J=8.22 Hz, 2H) 8.39 (d, J=1.76 Hz, 1H) 8.67 (d, J=1.76Hz, 1H);

MS (ESI, m/z): 542.3 [M+H]⁺

Example 4242-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide

Using morpholine, the title compound was obtained as described for theexample 423.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61(q, J=7.63 Hz, 2H) 3.09-3.27 (m, 2H) 3.31-3.40 (m, 2H) 3.46 (d, J=12.33Hz, 1H) 3.52-3.67 (m, 2H) 3.76 (br dd, J=12.91, 7.04 Hz, 1H) 3.77 (br s,2H) 4.03 (br s, 2H) 4.35 (br d, J=4.11 Hz, 1H) 4.41 (s, 2H) 4.63-4.71(m, 2H) 4.72 (br d, J=6.46 Hz, 1H)7.06-7.12 (m, 2H) 7.17 (s, 1H) 7.63(d, J=8.22 Hz, 2H) 7.82 (d, J=8.22 Hz, 2H) 8.40 (d, J=2.35 Hz, 1H)8.66-8.70 (m, 1H); MS (ESI, m/z): 530.3 [M+H]⁺

Example 4252-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 3,3-difluoropiperidine, the title compound was obtained asdescribed for the example 423.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 1.97-2.09 (m, 2H)2.15 (br s, 2H) 2.25 (s, 3H) 2.61 (q, J=7.63 Hz, 2H) 3.22-3.28 (m, 2H)3.38-3.49 (m, 4H) 3.50-3.66 (m, 2H) 3.76 (dd, J=12.33, 7.04 Hz, 1H) 4.35(br d, J=4.70 Hz, 1H) 4.40 (s, 2H) 4.62-4.73 (m, 3H) 7.07-7.12 (m, 2H)7.17 (s, 1H) 7.61 (d, J=8.22 Hz, 2H) 7.81 (d, J=8.22 Hz, 2H) 8.40 (d,J=2.35 Hz, 1H) 8.61 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 564.3 [M+H]⁺

Example 4262-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 426:

To compound 388 (40 mg, 0.09 mmol) in 0.4 ml of 1,2-dichloroethane wasadded formaldehyde (0.015 ml, 0.18 mmol) followed by NaBH(OAc)₃ (38 mg,0.28 mmol). The mixture was stirred at room temperature for 1 hr andthen water was added. The mixture was extracted with EtOAc, washed withbrine, dried over MgSO₄, and concentrated in vacuo. The crude residuewas purified by preparative HPLC to afford 30 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.12-1.17 (m, 3H) 2.23 (s, 3H) 2.55-2.65(m, 2H) 3.01 (s, 3H) 3.43-3.54 (m, 1H) 3.60-3.71 (m, 1H) 3.73-3.84 (m,1H) 3.92 (s, 3H) 4.08-4.23 (m, 1H) 4.31-4.45 (m, 1H) 4.62-4.70 (m, 2H)4.72 (br d, J=5.87 Hz, 1H) 7.04-7.11 (m, 2H) 7.15 (s, 1H) 7.88 (s, 1H)8.05 (s, 1H) 8.26 (d, J=2.35 Hz, 1H) 8.66 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 449.3 [M+H]⁺

Example 4272-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using benzaldehyde, the title compound was obtained as described for theexample 426.

MS (ESI, m/z): 525.7 [M+H]⁺

Example 4282-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-phenylpropanal, the title compound was obtained as described forthe example 426.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.14 (t, J=7.63 Hz, 3H) 1.97-2.13 (m, 2H)2.22 (s, 3H) 2.58 (q, J=7.63 Hz, 2H) 2.70 (t, J=7.63 Hz, 2H) 3.27 (t,J=7.63 Hz, 2H) 3.43-3.54 (m, 1H) 3.60-3.71 (m, 1H) 3.73-3.84 (m, 1H)3.92 (s, 3H) 4.08-4.23 (m, 1H) 4.36 (br s, 1H) 4.6-4.72 (m, 3H)7.01-7.10 (m, 2H) 7.12-7.15 (m, 1H) 7.15-7.30 (m, 5H) 7.87 (s, 1H) 8.04(s, 1H) 8.25 (d, J=1.76 Hz, 1H) 8.64 (br s, 1H); MS (ESI, m/z): 553.3[M+H]⁺

Example 4292-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using phenylacetaldehyde, the title compound was obtained as describedfor the example 426.

MS (ESI, m/z): 539.3[M+H]⁺

Example 4302-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using isobutyraldehyde, the title compound was obtained as described forthe example 426.

¹H NMR (600 MHz, CD₃OD) δ ppm 1.04 (br d, J=3.52 Hz, 6H) 1.14 (t, J=7.63Hz, 3H) 2.10 (dt, J=13.65, 6.97 Hz, 1H) 2.22 (s, 3H) 2.58 (q, J=7.63 Hz,2H) 3.14 (br d, J=6.46 Hz, 2H) 3.32-3.42 (m, 1H) 3.52 (br s, 1H)3.70-3.83 (m, 1H) 3.93 (s, 3H) 3.99-4.17 (m, 1H) 4.41 (br d, J=16.43 Hz,1H) 4.59-4.75 (m, 3H) 7.02-7.12 (m, 2H) 7.15 (br s, 1H) 7.87 (br s, 1H)8.05 (br d, J=11.15 Hz, 1H) 8.28 (d, J=1.76 Hz, 1H) 8.59 (br s, 1H);

MS (ESI, m/z): 491.3 [M+H]⁺

Example 4312-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)-oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using butyraldehyde, the title compound was obtained as described forthe example 426.

MS (ESI, m/z): 491.4 [M+H]⁺

Example 4322-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using acetaldehyde, the title compound was obtained as described for theexample 426.

MS (ESI, m/z): 463.3 [M+H]⁺

Example 4332-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

From compound 359, the title compound was obtained as described for theexample 426.

MS (ESI, m/z): 532.3 [M+H]⁺

Example 434 and Example 435

Scheme for the preparation of the Compounds of Example 434 and 435:

Intermediate 32

To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine(0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol)followed by tert-butyl(3S,4S)-3-amino-4-((4-bromobenzyl)oxy)pyrrolidine-1-carboxylate (657 mg,1.76 mmol). The mixture was stirred at room temperature for 1 hr andthen saturated sodium bicarbonate solution was added. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified through silicagelcolumn chromatography to give 700 mg of off-white solid.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.43 (br s, 9H) 3.42 (br d, J=10.56 Hz,1H) 3.51-3.65 (m, 2H) 3.80 (dd, J=12.03, 5.58 Hz, 1H) 3.89 (s, 3H)4.03-4.20 (m, 1H) 4.54-4.77 (m, 3H) 6.29 (br s, 2H) 7.25 (br d, J=8.22Hz, 2H) 7.46 (br d, J=8.22 Hz, 2H) 7.53 (br s, 1H) 7.57-7.67 (m, 2H)8.29 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 571.2 [M+H]⁺

Example 4342-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide

To a mixture of intermediate 32 (40 mg, 0.07 mmol) and4-((4-methylpiperazin-1-yl)-methylphenylboronic acid pinacol ester (27mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/water (3/1) was added K₂CO₃ (29mg, 0.21 mmol) followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol) Pd(PPh₃)₄. Thereaction mixture was heated at 100° C. for 3 hrs, cooled to roomtemperature, and extracted with EtOAc, dried over anhydrous MgSO₄ andconcentrated under vacuum. The crude residue was dissolved with 0.5 mlof CH₂Cl₂/TFA (10/1) and the mixture was stirred for 2 hrs. Afterconcentration under vacuum, the crude residue was purified bypreparative HPLC to afford 30 mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 2.88 (s, 3H) 2.91-3.13 (m, 4H) 3.31-3.46(m, 4H) 3.52-3.65 (m, 3H) 3.80 (dd, J=12.91, 7.04 Hz, 1H) 3.87-3.96 (m,5H) 4.39-4.45 (m, 1H) 4.71-4.83 (m, 3H) 7.46 (br d, J=8.22 Hz, 2H) 7.49(br d, J=8.22 Hz, 2H) 7.62 (dd, J=8.22, 2.35 Hz, 4H) 7.87 (s, 1H) 8.04(s, 1H) 8.25 (d, J=1.76 Hz, 1H) 8.65 (d, J=1.76 Hz, 1H);

MS (ESI, m/z): 581.4 [M+H]⁺

Example 4352-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide

To a mixture of compound 434 (52 mg, 0.09 mmol) in 0.4 ml of1,2-dichloroethane was added formaldehyde (0.015 ml, 0.18 mmol) followedby NaBH(OAc)₃ (38 mg, 0.28 mmol). The mixture was stirred at roomtemperature for 1 hr and then water was added. The mixture was extractedwith EtOAc, washed with brine, dried over MgSO₄, and concentrated invacuo. The crude residue was purified by preparative HPLC to afford 35mg of the title compound.

¹H NMR (600 MHz, CD₃OD) δ ppm 2.94 (s, 3H) 3.04 (s, 3H) 3.36-3.47 (m,6H) 3.48-3.58 (m, 6H) 3.91 (s, 3H) 4.27 (s, 2H) 4.44 (br s, 1H)4.72-4.83 (m, 3H) 7.49 (d, J=8.22 Hz, 2H) 7.53 (d, J=8.22 Hz, 2H) 7.61(d, J=8.22 Hz, 2H) 7.66 (d, J=8.22 Hz, 2H) 7.86 (s, 1H) 8.03 (s, 1H)8.22 (d, J=1.76 Hz, 1H) 8.67 (d, J=2.35 Hz, 1H);

MS (ESI, m/z): 595.3 [M+H]⁺

Example 4362-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-pyrrolidin-3-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 434.

MS (ESI, m/z): 649.3 [M+H]⁺

Example 4372-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-methoxy)pyrrolidin-3-yl)nicotinamide

From compound 436, the title compound was obtained as described for theexample 435.

MS (ESI, m/z): 663.3 [M+H]⁺

Example 4382-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide

Using (4-acetylphenyl)boronic acid, the title compound was obtained asdescribed for the example 434.

MS (ESI+) m/z 595.3 [M+H]⁺

Example 4392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide

From compound 438, the title compound was obtained as described for theexample 435.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (d, J=7.04 Hz, 3H) 2.90 (s, 3H) 3.05(s, 3H) 3.08-3.17 (m, 2H) 3.46 (br s, 4H) 3.93 (s, 3H) 4.16 (br d,J=6.65 Hz, 2H) 4.49 (s, 1H) 4.75-4.87 (m, 3H) 7.51 (dd, J=8.22, 4.70 Hz,4H) 7.57-7.70 (m, 4H) 7.88 (s, 1H) 8.05 (s, 1H) 8.26 (d, J=1.96 Hz, 1H)8.68 (d, J=1.96 Hz, 1H); MS (ESI+) m/z 609.4 [M+H]⁺

Example 4402-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)boronicacid pinacol ester, the title compound was obtained as described for theexample 434.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.77 (s, 6H) 3.50-3.68 (m, 6H) 3.80 (s,1H) 3.83-3.89 (m, 2H) 3.92 (s, 3H) 4.42 (br d, J=4.30 Hz, 1H) 4.73-4.88(m, 3H) 7.52 (d, J=8.22 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.67-7.84 (m,3H) 7.86-7.92 (m, 1H) 8.06 (s, 1H) 8.26 (d, J=2.35 Hz, 1H) 8.70 (d,J=2.35 Hz, 1H);

MS (ESI, m/z): 639.4 [M+H]⁺

Example 4412-amino-N-((3S,4S)-4-((4′-((2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

From compound 440, the title compound was obtained as described for theexample 435.

MS (ESI, m/z): 653.4 [M+H]⁺

Example 4422-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)boronic acidpinacol ester, the title compound was obtained as described for theexample 434.

MS (ESI, m/z): 625.4 [M+H]⁺

Example 4432-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

From compound 442, the title compound was obtained as described for theexample 435.

MS (ESI, m/z): 639.4 [M+H]⁺

Example 4442-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-boronicacid pinacol ester, the title compound was obtained as described for theexample 434.

MS (ESI, m/z): 679.3 [M+H]⁺

Example 4452-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-(4-bromo-2-(trifluoromethyl)benzyl)piperazine, the titlecompound was obtained as described for the example 435.

MS (ESI, m/z): 693.3 [M+H]⁺

Example 4462-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acidpinacol ester, the title compound was obtained as described for theexample 434.

MS (ESI, m/z): 611.3 [M+H]⁺

Example 4472-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

From compound 446, the title compound was obtained as described for theexample 435.

MS (ESI, m/z): 625.4 [M+H]⁺

Example 4482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-nicotinamide

Scheme for the preparation of the Compound of Example 448:

Intermediate 33

Using intermediate 2 and(3S,4R)-4-((4-bromobenzyl)oxy)tetrahydrofuran-3-amine, the titlecompound was obtained as described for the intermediate 4.

¹H NMR (600 MHz, CD₃OD) δ ppm 3.81 (td, J=10.27, 2.35 Hz, 2H) 3.91 (s,3H) 4.05 (dd, J=9.98, 5.28 Hz, 1H) 4.11 (dd, J=9.39, 5.87 Hz, 1H)4.13-4.16 (m, 1H) 4.55 (dd, J=3.81, 2.05 Hz, 1H) 4.60 (s, 2H) 4.63 (d,J=12.33 Hz, 1H) 4.74 (d, J=12.33 Hz, 1H) 7.30 (m, J=8.22 Hz, 2H)7.45-7.49 (m, 2H) 7.78 (s, 1H) 7.90 (s, 1H) 8.07 (d, J=2.35 Hz, 1H) 8.26(d, J=1.76 Hz, 1H);

MS (ESI, m/z): 472.1 [M+H]⁺

Example 4482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-nicotinamide

Using intermediate 33, the title compound was obtained as described forthe example 172.

¹H NMR (600 MHz, CD₃OD) δ ppm 2.87 (s, 3H) 3.80-3.89 (m, 4H) 3.92 (s,3H) 4.04-4.15 (m, 2H) 4.19-4.25 (m, 1H) 4.57-4.63 (m, 1H) 4.71 (d,J=11.74 Hz, 1H) 4.82 (d, J=11.74 Hz, 1H) 7.40-7.51 (m, 4H) 7.57-7.63 (m,4H) 7.88 (s, 1H) 8.02 (s, 1H) 8.23 (s, 1H) 8.62 (s, 1H);

MS (ESI, m/z): 582.3 [M+H]⁺

Example 4492-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol esterpinacol ester, the title compound was obtained as described for theexample 448.

¹H NMR (400 MHz, CD₃OD) δ ppm 2.91 (s, 3H) 3.80-3.91 (m, 3H) 3.94 (s,2H) 4.12 (td, J=9.59, 5.48 Hz, 2H) 4.23 (br s, 1H) 4.62 (br s, 1H) 4.74(d, J=12.13 Hz, 1H) 7.52 (d, J=8.61 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.88(d, J=13.30 Hz, 4H) 8.03 (s, 1H) 8.25 (d, J=1.96 Hz, 1H) 8.63 (d, J=1.96Hz, 1H); MS (ESI, m/z): 650.3 [M+H]⁺

Example 4502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester,the title compound was obtained as described for the example 448.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (s, 6H) 2.89 (s, 3H) 3.04 (br s, 2H)3.34-3.47 (m, 4H) 3.82-3.91 (m, 2H) 3.93 (s, 3H) 4.12 (td, J=10.56, 5.48Hz, 2H) 4.22 (br s, 1H) 4.61 (br s, 1H) 4.66-4.77 (m, 1H) 4.81-4.88 (m,1H) 7.47 (d, J=7.83 Hz, 2H) 7.58-7.70 (m, 6H) 7.89 (s, 1H) 8.03 (s, 1H)8.24 (d, J=1.96 Hz, 1H) 8.65 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 610.2 [M+H]⁺

Example 4512-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acidpinacol ester, the title compound was obtained as described for theexample 448.

MS (ESI, m/z): 612.3 [M+H]⁺

Example 4522-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-boronicacid pinacol ester, the title compound was obtained as described for theexample 448.

¹H NMR (400 MHz, CD3OD) δ ppm 2.62 (br s, 4H) 3.25-3.29 (m, 2H)3.34-3.40 (m, 2H) 3.82-3.84 (m, 2H) 3.85-3.91 (m, 2H) 3.94 (s, 2H)4.06-4.17 (m, 2H) 4.23 (br s, 1H) 4.62 (br s, 1H) 4.74 (m, 1H) 7.52 (m,J=8.22 Hz, 2H) 7.65 (m, J=8.22 Hz, 2H) 7.86 (s, 2H) 7.89 (s, 2H) 8.03(s, 1H) 8.25 (d, J=1.96 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H);

MS (ESI, m/z): 680.3 [M+H]⁺

Example 4532-amino-N-((3S,4R)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)boronicacid pinacol ester, the title compound was obtained as described for theexample 448.

MS (ESI, m/z): 640.2 [M+H]⁺

Example 4542-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl-nicotinamide

Usingtrans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-amine,the title compound was obtained as described for the example 448.

¹H NMR (400 MHz, CD₃OD) δ ppm 2.88 (s, 3H) 3.76-3.89 (m, 4H) 4.09 (ddd,J=16.92, 9.88, 5.28 Hz, 2H) 4.20 (br d, J=4.70 Hz, 1H) 4.57 (br s, 1H)4.70 (br d, J=11.74 Hz, 1H) 6.98 (dd, J=7.43, 6.26 Hz, 1H) 7.46 (d,J=8.22 Hz, 4H) 7.56-7.67 (m, 4H) 7.99-8.06 (m, 1H) 8.40 (dd, J=7.43,1.56 Hz, 1H);

MS (ESI, m/z): 582.3 [M+H]⁺

Example 4552-amino-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

Using 2-aminonicotinic acid andtrans-4-((4-bromobenzyl)oxy)tetrahydrofuran-3-amine, the title compoundwas obtained as described for the example 448.

¹H NMR (400 MHz, CD₃OD) δ ppm 2.88 (s, 3H) 3.76-3.89 (m, 4H) 4.09 (ddd,J=16.92, 9.88, 5.28 Hz, 2H) 4.20 (br d, J=4.70 Hz, 1H) 4.57 (br s, 1H)4.70 (br d, J=11.74 Hz, 1H) 6.98 (dd, J=7.43, 6.26 Hz, 1H) 7.46 (d,J=8.22 Hz, 4H) 7.56-7.67 (m, 4H) 7.99-8.06 (m, 1H) 8.40 (dd, J=7.43,1.56 Hz, 1H);

MS (ESI, m/z): 502.3 [M+H]⁺

Example 4562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamide

Scheme for the preparation of the Compound of Example 456:

Intermediate 34

To a suspension of methyl 2-amino-6-chloronicotinate (100 mg, 0.54 mmol)in 3 ml of MeOH was added 2N NaOH (1 ml, 2 mmol) and the mixture washeated at 65° C. for 1 hr, cooled to room temperature, neutralized (1 mlof 2N HCl), and the resulting precipitate was filtered, washed withMeOH, and dried to give 80 mg of off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.61 (d, J=7.83 Hz, 1H) 7.53 (br s, 2H)8.01 (d, J=8.22 Hz, 1H); MS (ESI, m/z): 173.2 [M+H]⁺

Intermediate 35

To a mixture of intermediate 34 (50 mg, 0.29 mmol) and triethylamine(0.061 ml, 0.43 mmol) in 2 ml of DMF was added HATU (132 mg, 0.35 mmol)followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (55 mg, 0.29 mmol).The mixture was stirred at room temperature for 1 hr and then saturatedsodium bicarbonate solution was added. The mixture was extracted withEtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo.The crude residue was purified by preparative HPLC to afford 80 mg ofthe title compound.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.39-1.52 (m, 1H) 1.68-1.81 (m, 2H)1.83-1.89 (m, 1H) 1.89-2.02 (m, 1H) 2.27 (td, J=13.69, 7.83 Hz, 1H)3.80-3.87 (m, 1H) 4.27-4.37 (m, 1H) 4.58-4.67 (m, 2H) 5.79 (br d, J=6.26Hz, 1H) 6.51 (br s, 2H) 6.56 (d, J=7.83 Hz, 1H) 7.25-7.37 (m, 5H) 7.39(d, J=7.83 Hz, 1H);

MS (ESI, m/z): 345.3 [M+H]⁺

Example 4562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamide

To a mixture of intermediate 35 (186 mg, 1 mmol) and4-((4-methylpiperazine-1-yl)methyl)aniline (240 mg, 1.2 mmol) in 5 ml of1,4-dioxane was added 480 mg of K₂CO₃ followed by Pd₂(dba)₃ (30 mg, 0.3mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled toroom temperature, and extracted with EtOAc, dried over anhydrous MgSO₄and concentrated under vacuum. The crude product was purified bysilicagel column chromatography to give 170 mg of off-white solid.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.57 (br dd, J=13.30, 7.04 Hz, 1H)1.66-1.87 (m, 3H) 1.97 (dt, J=13.01, 6.60 Hz, 1H) 2.13 (br dd, J=13.11,6.85 Hz, 1H) 2.95 (s, 3H) 3.44-3.62 (m, 4H) 3.87-3.97 (m, 1H) 4.17 (s,2H) 4.31-4.39 (m, 1H) 4.60 (s, 2H) 6.25 (d, J=9.00 Hz, 1H) 7.21-7.35 (m,4H) 7.43 (d, J=8.22 Hz, 2H) 7.58 (d, J=8.61 Hz, 2H) 8.08 (d, J=9.00 Hz,1H); MS (ESI, m/z): 515.3 [M+H]⁺

Example 4572-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(phenylamino)-nicotinamide

Using aniline, the title compound was obtained as described for theexample 456.

MS (ESI, m/z): 403.2 [M+H]⁺

Example 4582-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)nicotinamide

Using 4-(4-methylpiperazin-1-yl)aniline, the title compound was obtainedas described for the example 456.

MS (ESI, m/z): 501.3 [M+H]⁺

Biochemical Assay

For the SAR (structure-activity relationship) and compound screening,LanthaScreen™ TR-FRET (Time-Resolved fluorescence energy transfer) assaywas employed using the phospho-tyrosine specific Terbium (Tb)-labeldedantibody with a fluorescein labeled poly-GT (glutamate-tyrosine) as asubstrate. Upon excitation at 340 nm by UV, the energy from Tb donor ofthe antibody is transferred to the fluorescein of the phosphorylatedpoly GT substrate, and fluorescein emits light at 520 nm. The ratiobetween the intensity of primary emission at 495 nm and that ofsecondary emission at 520 nm was used to quantify the level of kinaseactivity. The recombinant proteins of human c-MER and AXL catalyticdomains, Fluorescein-labeled poly-GT substrate, Tb-labeledanti-phosphorylated tyrosine antibodies, the kinase assay buffer, and0.5M EDTA solution were purchased (Life technologies, USA). The TR-FRETassays were carried out in the white low volume 384-well plate (Corning,USA). To measure the compound mediated inhibition of kinase activity,the recombinant kinases were pre-incubated with test compounds for 20minutes prior to the addition of 200 nM fluorescein labeled poly-GTsubstrates and 10 uM ATP, and then the reaction was carried out for 1hour at room temperature. 10 mM EDTA was added to terminate the enzymereaction, and the level of phosphorylation of poly-GT substrate wasdetermined following 30 min incubation with 2 nM Tb-labeled antibody.The fluorescence intensity was measured with Envision™ plate reader(PerkinElmer, USA).

In Cell MER Kinase Assay Using BaF3 Cellular System

CD8-MerTK is a chimeric fusion protein consisting of the extracellularand transmembrane domains of the human CD8a (amino acids 1 to 209) atits N-terminus and the kinase domain and intracellular parts of MerTK(amino acids 521-994) at its C-terminus. To establish an in cell kinaseassay for MerTK kinase, the IL-3 dependent Ba/F3 cells of murinelymphoid origin was transfected with CD8-MerTK. The resulting Ba/F3-CDMline was then validated that Ba/F3-CDM cell proliferation is completelydependent on the activity of MerTK kinase activity when growing in theabsence of IL-3. For a routine cellular assay, Ba/F3-CDM cells wereseeded at 2,000 cells per well in 384-well cell culture plate containingDMEM/10% FBS culture media and incubated for 24 hours before addition ofcompounds pre-diluted in culture media. Following compound treatment,cells were further incubated for 48 hours and the proliferation wasmeasured. To discriminate a Ba/F3 growth inhibition by a specificinhibition of MerTK kinase following compound treatment vs growthinhibition due to a non-specific unintended cytotoxicity of compounds,we routinely carried out control sets of Ba/F3 cells in parallel thatgrown in IL3-supplemented growth media. In the presence of IL-3, theproliferation of Ba/F3 is no longer dependent on the MerTK activity.Cell growth and proliferation was measured with Celltiter-Glo™ system(Promega, USA) according to the manufacturer's instruction. Thehalf-maximal growth inhibitory concentration (GI₅₀) value was calculatedwith Prism6.0 software (GraphPad, USA).

TABLE 1 Biochemical IC50 and cell growth inhibitory GI50 values. Cellgrowth inhibition Compound No. Mer TK inhibition (IC50) (GI50) 1 +++ + 2++ 3 ++ 4 + 5 + 6 +++ 7 +++ 8 +++ 9 +++ 10 ++ 11 +++ 12 ++ 13 +++ 14 +++15 + + 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 ++++ + 22 +++ 23 ++ + 24+++ 25 +++ 26 ++ 27 ++ 28 ++ 29 ++ 30 + 31 + 32 + 33 ++ 34 ++ 35 + 36 +37 ++ 38 ++ 39 ++ 40 ++ 41 +++ 42 + 43 ++ 44 ++ + 45 ++ 46 ++ 47 ++ 48++ 49 ++ 50 + 51 + 52 ++ 53 + 54 ++ 55 + 56 + 57 + 58 + 59 + 60 ++ 61 ++62 + 63 +++ + 64 ++ 65 +++ ++ 66 + 67 ++ 68 +++ + 69 + 70 + 71 + 72 +73 + 74 + 75 + 76 + 77 ++ 78 +++ + 79 + 80 ++ 81 +++ + 82 ++ 83 + 84 ++85 ++ 86 ++++ +++ 87 ++ 88 ++ 89 ++ 90 + 91 + 92 + 93 ++ + 94 + 95 +96 + 97 + 98 + 99 + 100 + 101 ++ 102 + 103 + 104 + 105 + 106 + 107 +108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 +120 + 121 + 122 + 123 + 124 + 125 + 126 + 127 + 128 + 129 + 130 +++ +131 + 132 ++ 133 + 134 +++ 135 +++ + 136 ++++ +++ 137 ++++ ++++ 138++++ + 139 + 140 +++ 141 +++ 142 ++++ +++ 143 + 144 ++++ ++ 145 ++++ +146 ++++ ++++ 147 ++++ +++ 148 ++++ + 149 +++ + 150 +++ + 151 +++ 152+++ 153 ++++ ++ 154 ++ + 155 +++ + 156 ++++ ++++ 157 ++++ +++ 158 ++ +159 ++++ +++ 160 +++ +++ 161 ++++ ++++ 162 +++ 163 ++ 164 + + 165 +166 + 167 ++++ 168 ++ + 169 + 170 + 171 + 172 ++++ ++++ 173 +++ + 174++++ +++ 175 +++ + 176 +++ + 177 ++++ +++ 178 ++ + 179 ++++ +++ 180++++ + 181 ++++ ++++ 182 ++++ ++++ 183 ++++ ++++ 184 ++++ ++++ 185 +++++++ 186 ++++ ++++ 187 ++++ ++++ 188 ++++ ++++ 189 ++++ +++ 190 ++++ ++++191 ++++ +++ 192 ++++ ++++ 193 ++++ ++++ 194 ++++ ++++ 195 ++++ ++++ 196++++ +++ 197 ++++ ++++ 198 ++++ ++++ 199 ++++ ++++ 200 ++++ +++ 201 ++++++ 202 ++++ +++ 203 ++++ +++ 204 ++++ 205 ++++ ++++ 206 ++++ +++ 207++++ 208 ++++ ++++ 209 ++++ ++++ 210 ++++ ++++ 211 ++++ ++++ 212 ++++ +213 ++++ +++ 214 ++++ ++++ 215 ++++ ++++ 216 ++++ ++++ 217 ++++ ++++ 218++++ ++++ 219 ++++ ++++ 220 ++++ ++++ 221 ++++ ++++ 222 ++++ ++++ 223++++ +++ 224 ++++ +++ 225 ++++ +++ 226 ++++ ++++ 227 ++++ ++++ 228 +++++++ 229 ++++ ++++ 230 ++++ ++++ 231 ++++ 232 ++++ ++ 233 ++++ +++ 234 ++235 ++++ ++ 236 ++++ ++++ 237 ++++ ++++ 238 ++++ ++++ 239 ++++ ++++ 240++++ ++++ 241 ++++ ++ 242 ++++ ++++ 243 ++ + 244 + 245 ++++ ++ 246 +++++++ 247 ++++ +++ 248 +++ + 249 ++++ + 250 ++++ +++ 251 ++++ + 252 +++ +253 +++ + 254 +++ + 255 +++ ++ 256 +++ 257 +++ + 258 +++ 259 ++ 260 +++261 ++ 262 + 263 + 264 + 265 ++ 266 ++ 267 + 268 ++ 269 ++ 270 +++ 271+++ 272 +++ 273 +++ + 274 +++ 275 +++ ++ 276 +++ 277 +++ 278 +++ 279 +++280 +++ 281 +++ 282 +++ 283 +++ 284 +++ 285 +++ 286 +++ 287 ++ + 288 ++289 +++ 290 +++ 291 +++ 292 +++ 293 +++ + 294 ++ 295 ++ 296 ++ 297 +++ +298 ++ 299 +++ 300 +++ 301 +++ 302 +++ + 303 +++ 304 +++ 305 ++ 306 +++307 +++ 308 ++ 309 ++ 310 ++ 311 +++ 312 +++ 313 +++ + 314 +++ 315 +++316 +++ 317 ++ 318 ++++ ++ 319 +++ 320 +++ 321 +++ + 322 +++ 323 +++ 324+++ 325 ++++ + 326 +++ 327 ++++ + 328 ++++ ++ 329 ++++ 330 ++++ 331+++ + 332 +++ 333 +++ + 334 ++ 335 ++ 336 ++ 337 ++++ ++ 338 +++ + 339+++ 340 +++ + 341 +++ 342 ++++ 343 +++ 344 +++ 345 +++ 346 +++ + 347++++ + 348 ++++ + 349 +++ + 350 +++ 351 +++ 352 +++ + 353 +++ 354 ++ 355+++ + 356 +++ + 357 +++ + 358 +++ + 359 +++ + 360 ++++ + 361 +++ + 362 +363 ++++ +++ 364 ++++ ++++ 365 +++ + 366 ++++ ++++ 367 ++++ ++++ 368++++ ++++ 369 ++++ ++++ 370 ++++ ++++ 371 ++++ ++++ 372 ++++ ++++ 373++++ +++ 374 ++++ +++ 375 ++++ ++++ 376 ++++ ++++ 377 ++++ ++++ 378 ++++++++ 379 ++++ ++++ 380 ++++ ++++ 381 ++++ ++++ 382 ++++ 383 ++++ ++++384 ++++ ++++ 385 ++++ +++ 386 ++++ ++++ 387 ++++ ++++ 388 ++++ +++ 389++++ +++ 390 ++++ +++ 391 ++++ + 392 +++ + 393 ++ + 394 ++++ ++ 395 ++++++ 396 ++++ + 397 +++ + 398 +++ ++ 399 ++++ ++ 400 ++++ ++ 401 ++++ +402 ++ + 403 ++ ++ 404 ++ + 405 ++++ +++ 406 +++ + 407 +++ ++ 408 +++ +409 +++ + 410 +++ + 411 ++++ +++ 412 ++++ + 413 ++++ ++ 414 +++ + 415++++ + 416 ++++ +++ 417 +++ ++ 418 +++ ++ 419 ++++ + 420 +++ + 421 +++ +422 +++ + 423 +++ ++ 424 +++ + 425 +++ ++ 426 ++++ ++ 427 +++ + 428+++ + 429 ++ + 430 +++ + 431 +++ + 432 +++ 433 ++++ +++ 434 ++++ ++ 435++++ +++ 436 ++++ ++ 437 ++++ ++++ 438 ++++ ++ 439 ++++ +++ 440 ++++ +441 ++++ +++ 442 ++++ + 443 ++++ ++++ 444 ++++ + 445 ++++ ++++ 446++++ + 447 ++++ ++++ 448 ++++ ++++ 449 ++++ ++++ 450 ++++ ++++ 451 ++++++++ 452 ++++ ++++ 453 ++++ +++ 454 ++++ 455 +++ 456 + 457 + 458 + ++++:IC50 < 10, +++: 10 ≦ IC50 < 100, ++: 100 ≦ IC50 < 1000, +: IC50 ≧ 1000nM ++++: GI50 < 100, +++: 100 ≦ GI50 < 500, ++: 500 ≦ GI50 < 1000, +:GI50 ≧ 1000 nM

As can be seen in Table 1 above, the heterocyclic compounds of thepresent invention showed the activity of Mer, which compounds are usefulfor the prevention and/or the treatment of cancer.

1. A heterocyclic compound represented by the following Formula I, astereoisomer thereof, an enantiomer thereof, or a pharmaceuticallyacceptable salt thereof:

wherein: X is CR⁷, or N; Y is CHR⁸, NR⁸, or O; Z is CH₂, CH₂O, C(═O),C(═O)O, C(═O)NH, NR⁸ NHC(═O), O or O(C═O); R¹ is H, halogen, C₁₋₃ alkyl,NHR⁸ or OR⁸; R² is H, halogen, C₁₋₄ alkyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, C₁₋₂ alkylheterocyclyl or -L-aryl, which C₁₋₂alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂ alkylheterocyclyl or -L-aryl mayoptionally be substituted with one or more R⁹; R³ is H, halogen, CN,C₁₋₃ alkyl, cycloalkenyl, C₂₋₆ alkenyl, aryl, biaryl, heteroaryl,heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, orC₁₋₂ alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl,heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, or C₁₋₂alkylheterocyclyl may optionally be substituted with one or more R⁹; R⁴and R⁵ each independently is H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₁₀cycloalkyl, C(═O) R⁶, C₁₋₂ alkylaryl, aryl; or R⁴ and R⁵ may be combinedwith each other to form a 3-7 membered cyclic ring or heterocyclic ringcontaining 1 or 2 of NR⁸, O or S, and the cyclic or heterocyclic ringmay optionally be substituted with 1 or 2 halogen(s), C₁₋₄ alkyl or C₁₋₄alkoxy; R^(5′) is H or R⁵ and R^(5′) may be combined with each other toform carbonyl; R⁶ is H, C₁₋₄ alkyl, C₁₋₆ alkoxy, —NR¹⁵R¹⁶, aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, C₁₋₂ alkylheterocyclyl, C₁₋₂ alkylbiaryl, -L-aryl or-L-biaryl, which C₁₋₄ alkyl, aryl, biaryl, heteroaryl, heterobiaryl,heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂alkylheterocyclyl, C₁₋₂ alkylbiaryl, -L-aryl or -L-biaryl, mayoptionally be substituted with one or more R⁹; R⁷ is H, halogen or C₁₋₃alkyl; R⁸ is H, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃alkylaryl or C(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionallybe substituted with one or more R⁹; when Z is NR⁸, R⁸ and R⁶ may becombined with each other to form a 3-7 membered heterocyclic ringcomprising 1 to 2 N or 0 to 2 O heteroatoms; R⁹ is halogen, hydroxyl,—CN, —NO₂, —COOH, —(C═O)H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —NR¹⁵R¹⁶, -L-NR¹⁵R¹⁶, -L-COOR¹⁷, -L-alkyl,-L-C₃₋₁₀ cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl whichC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl,-L-alkyl, -L-C₃₋₁₀ cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or-L-aryl may substituted with halogen, hydroxyl, —CN, —NR¹⁵R¹⁶, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₂₋₆ alkenyl, aryl,heterocyclyl, -L-heterocyclyl, or —(CH₂)_(l)—C(═O)—NR¹⁵R¹⁶; R¹⁰ is C₁₋₃alkyl or C₁₋₃ alkylaryl; R¹⁵ and R¹⁶ each independently is H, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl or SO₂R¹⁷; R¹⁷ is H, C₁₋₃alkyl or C₁₋₃alkylaryl; L is C₁₋₃ alkyl, C₁₋₃ alkylO, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,—(CH₂)₁—C(═O)—(CH₂)_(m)—, C(═O)O, —(CH₂)_(l)—C(═O)NH—(CH₂)_(m)—,—(CH₂)_(l)—NHC(═O)—(CH₂)_(m)—, —(CH₂)_(l)—NH—(CH₂)_(m),NR⁸—NH—C(═O)—CR¹⁵R¹⁶—NH—C(═O)—, NHC(═O), O, O(C═O) S, S(═O), or SO₂; andl and m each independently is an integer of 0 to
 2. 2. The heterocycliccompound, the stereoisomer thereof, the enantiomer thereof, or thepharmaceutically acceptable salt thereof of claim 1, wherein theheterocyclic compound represented formula I is represented by thefollowing Formula Ia:

wherein: X is CH, or N; Y is NR⁸, or O; W is CH₂, (CH₂)₂, NR¹¹, or O; Zis CH₂, CH₂O, C(═O), C(═O)O, C(═O)NH, NR⁸, NHC(═O), O or O(C═O); R³ isH, halogen, CN, C₁₋₃ alkyl, cycloalkenyl, C₂₋₆ alkenyl, aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl which aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl may optionally be substitutedwith one or more R⁹, R⁶ is H, C₁₋₄ alkyl, C₁₋₆ alkoxy, —NR¹⁵R¹⁶, aryl,biaryl, heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, C₁₋₂ alkylheterocyclyl, C₁₋₂ alkylbiaryl, -L-aryl or-L-biaryl, which C₁₋₄ alkyl, aryl, biaryl, heteroaryl, heterobiaryl,heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂ alkylheteroaryl, C₁₋₂alkylheterocyclyl, C₁₋₂ alkylbiaryl, -L-aryl or -L-biaryl, mayoptionally be substituted with one or more R⁹; R⁸ is H, C₁₋₆ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkylaryl or C(═O)R¹⁰ which C₁₋₆alkyl or C₁₋₃ alkylaryl may optionally be substituted with one or moreR⁹; when Z is NR⁸, R⁸ and R⁶ may be combined with each other to form a3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 Oheteroatoms; R⁹ is halogen, hydroxyl, —CN, —NO₂, —COOH, —(C═O)H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₆ alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR¹⁵R¹⁶,-L-NR¹⁵R¹⁶, -L-COOR¹⁷, -L-alkyl, -L-C₃₋₁₀ cycloalkyl, -L-heterocyclyl,-L-heteroaryl, or -L-aryl which C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl,heterocyclyl, heteroaryl, -L-alkyl, -L-C₃₋₁₀ cycloalkyl,-L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen,hydroxyl, —CN, —NR¹⁵R¹⁶, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₄hydroxyalkyl, C₂₋₆ alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or—(CH₂)_(l)—C(═O)—NR¹⁵R¹⁶; R¹⁰ is C₁₋₃ alkyl or C₁₋₃ alkylaryl; R¹¹ is H,C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkylaryl orC(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionally besubstituted with one or more R⁹; R¹⁵ and R¹⁶ each independently is H,C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl or SO₂R¹⁷; R¹⁷ is H, C₁₋₃ alkyl or C₁₋₃alkylaryl; R¹⁸ to R²¹ are the same as or different from each other, andare each independently H or halogen; or R¹⁸ and R¹⁹; or R²⁰ and R²¹ maybe combined with each other to form a 3-7 membered cyclic ring orheterocyclic ring containing 1 or 2 of NR⁸, O or S, and the cyclic orheterocyclic ring may optionally be substituted with 1 or 2 halogen(s),C₁₋₄ alkyl or C₁₋₄ alkoxy; L is C₁₋₃ alkyl, C₁₋₃ alkylO, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, —(CH₂)_(l)—C(═O)—(CH₂)_(m)—, C(═O)O,—(CH₂)₁—C(═O)NH—(CH₂)_(m)—, —(CH₂)_(l)—NHC(═O)—(CH₂)_(m)—,—(CH₂)₁—NH—(CH₂)_(m)—, NR⁸, —NH—C(═O)—CR¹⁵R¹⁶—NH—C(═O)—NHC(═O), O,O(C═O) S, S, S(═O), or SO₂; and l and m each independently is an integerof 0 to
 2. 3. The heterocyclic compound, the stereoisomer thereof, theenantiomer thereof, or the pharmaceutically acceptable salt thereof ofclaim 1, wherein the heterocyclic compound represented formula I isrepresented by the following Formula Ib:

wherein: X is CH, or N; W is CH₂, NR¹¹, or O; V¹ and V² eachindependently is CR¹³R^(13′) NR¹³ or O; at least one of V₁ and V₂ isCR¹³R^(13′); X¹ to X⁵ are the same as or different from each other, andare each independently CR¹⁴ or N; at least one of X¹ to X⁵ is CR¹⁴; R³is H, halogen, CN, C₁₋₃ alkyl, cycloalkenyl, C₂₋₆ alkenyl, aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl which aryl, biaryl,heteroaryl, heterobiaryl, heterocyclyl, C₁₋₂ alkylaryl, C₁₋₂alkylheteroaryl, or C₁₋₂ alkylheterocyclyl may optionally be substitutedwith one or more R⁹; R⁹ is halogen, hydroxyl, —CN, —NO₂, —COOH, —(C═O)H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄hydroxyalkyl, C₁₋₆ alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl,—NR¹⁵R¹⁶, -L-NR¹⁵R¹⁶, -L-COOR¹⁷, -L-alkyl, -L-C₃₋₁₀ cycloalkyl,-L-heterocyclyl, -L-heteroaryl, or -L-aryl which C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkoxy,cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C₃₋₁₀cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substitutedwith halogen, hydroxyl, —CN, —NR¹⁵R¹⁶, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,C₁₋₄ hydroxyalkyl, C₂₋₆ alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or—(CH₂)_(l)—C(═O)—NR¹⁵R¹⁶; R¹⁰ is C₁₋₃ alkyl or C₁₋₃ alkylaryl; R¹¹ is H,C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkylaryl orC(═O)R¹⁰ which C₁₋₆ alkyl or C₁₋₃ alkylaryl may optionally besubstituted with one or more R⁹; R¹³ and R^(13′) each independently isH, C₁₋₃ alkyl, C₂₋₃ hydroxyalkyl; each R¹⁴ is independently selectedfrom H, halogen, hydroxyl, —CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl,—NR¹⁵R¹⁶, -L-alkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl whichC₁₋₆ alkyl, aryl, heteroaryl, heterocyclyl may optionally be substitutedwith one or more R⁹; or adjacent groups among a plurality of R¹⁴s arebonded to each other to form a 3-7 membered cyclic ring or heterocyclicring containing 1 or 2 of NR¹¹ O or S, and the cyclic or heterocyclicring may optionally be substituted with 1 or 2 halogen(s), C₁₋₄ alkyl orC₁₋₄ alkoxy; R¹⁵ and R¹⁶ each independently is H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl or SO₂R¹⁷; R¹⁷ is H, C₁₋₃ alkyl or C₁₋₃ alkylaryl; L is C₁₋₃alkyl, C₁₋₃ alkylO, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,—(CH₂)_(l)—C(═O)—(CH₂)_(m)—, C(═O)O, —(CH₂)_(l)—C(═O)NH—(CH₂)_(m)—,—(CH₂)_(l)—NHC(═O)—(CH₂)_(m)—, —(CH₂)_(l)—NH—(CH₂)_(m)—,NR⁸—NH—C(═O)—CR¹⁵R¹⁶—NH—C(═O)—, NHC(═O), O, O(C═O) S, S, S(═O), or SO₂;and 1 and m each independently is an integer of 0 to
 2. 4. Theheterocyclic compound, the stereoisomer thereof, the enantiomer thereof,or the pharmaceutically acceptable salt thereof of claim 1, wherein theheterocyclic compound represented formula I is represented by any one ofthe following compounds: Example 12-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 22-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 32-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 42-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 52-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 62-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 72-amino-N-((1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 82-amino-N-((1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 92-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 102-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 112-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 122-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 132-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 142-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 152-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 162-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 172-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 182-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 192-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 202-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 212-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 222-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamide Example 232-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 242-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 252-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 262-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 272-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 282-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 292-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide Example 302-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamide Example 312-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 322-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 332-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 342-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 352-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 362-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 372-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 382-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamide Example 402-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 412-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamide Example 42 methyl3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate Example 432-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 442-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 452-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 462-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamid Example 472-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 482-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 492-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamide Example 512-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 522-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 532-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 542-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 55 methyl(3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoyl)glycinate Example 562-amino-N-((1S,2S)-2-((3-((2-hydroxyethyl)carbamoyl)benzyl)-oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 572-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)oxy)cyclopentyl)nicotinamide Example 582-amino-N-((1S,2S)-2-((3-((S)-2-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 59N-((1S,2S)-2-((3-((S)-2-acetamidopropanamido)benzyl)oxy)-cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 602-amino-N-((1S,2S)-2-((3-(3-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 61N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 62N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 632-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamide Example 642-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamide Example 652-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 66N-(trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 67N-((1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 68N-((1S,2S)-2-([1,1′-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 692-amino-N-((1S,2S)-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 702-amino-N-(cis-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 71N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 72N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-((3,4-dimethylbenzyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 732-amino-N-((6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 742-amino-N-(trans-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 752-amino-N-((1S,2S)-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 762-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 772-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamide Example 782-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 792-amino-N-(trans-2,2-difluoro-5-(phenoxymethyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 802-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 81 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamide Example 822-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)methyl)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 832-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide Example 842-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamide Example 852-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 862-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4′-((4-methyl-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentyl)-nicotinamide Example 87 (1S,2S)-2-(benzyloxy)cyclopentyl2-amino-5-(1-methyl-1H-pyrazol-4- yl)nicotinate Example 882-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamide Example 892-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 902-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-morpholinotetrahydrofuran-3-yl)nicotinamide Example 912-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)nicotinamide Example 922-amino-N-(cis-4-hydroxytetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 932-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 942-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 95(R)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 96(S)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 97(S)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 98(R)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 992-amino-N-(1-(benzyloxy)-2-methylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 100(R)-2-amino-N-(1-((3,4-dimethylbenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 101(S)-2-amino-N-(2-((3,4-dimethylbenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 102(R)-2-amino-N-(1-((4-chlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 103(S)-2-amino-N-(2-((4-chlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 104(R)-2-amino-N-(1-((3,4-dichlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 105(S)-2-amino-N-(2-((3,4-dichlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 106(R)-2-amino-N-(1-((3-methoxybenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 107(S)-2-amino-N-(2-((3-methoxybenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 108(R)-2-amino-N-(1-(benzyloxy)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 109(S)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 110(R)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 111(S)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 112(R)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 113(R)-2-amino-N-(2-(benzyloxy)-1-cyclohexylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 114(R)-2-amino-N-(1-cyclohexyl-2-hydroxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 115(S)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 116(R)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 117(S)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 118(R)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 119(R)-2-amino-N-(1-(cyclobutylmethoxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 120 methylN-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L- serinateExample 121 methylN-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-threoninate Example 1222-amino-N-((2S,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1232-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(propylamino)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1242-amino-N-((2S,3R)-3-(benzyloxy)-1-(cyclopentylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1252-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 126 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-alaninate Example 127benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-valinateExample 128 benzyl(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-serinate Example 1293-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 1303-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 131(S)-3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide Example 1323-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 1333-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 1342-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1352-amino-N-((1S,2S)-2-((4′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1362-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(methylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1372-amino-N-((1S,2S)-2-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example138 2-amino-N-((1S,2S)-2-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example139 2-amino-N-((1S,2S)-2-((3′-amino-2′-methyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example140 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example141 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example142 2-amino-N-((1S,2S)-2-((4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example143 2-amino-N-((1S,2S)-2-((3′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example144 2-amino-N-((1S,2S)-2-((4′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example145 2-amino-N-((1S,2S)-2-((4′-(2-aminoethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example1462-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1472-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 1482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamideExample 1492-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1512-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1522-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholine-4-carbonyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example1532-amino-N-((1S,2S)-2-((4′-ethyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1542-amino-N-((1S,2S)-2-((4′-(cyanomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example155 2-amino-N-((1S,2S)-2-((4′-carbamoyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example1562-amino-N-((1S,2S)-2-((3-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1572-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1582-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1592-amino-N-((1S,2S)-2-((2-chloro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1602-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1612-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1622-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 1632-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamideExample 164 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1652-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1662-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamide Example 1672-amino-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1682-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 169 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example1702-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1712-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example172 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1732-amino-N-((1S,2S)-2-((4′-(((2-hydroxyethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 174 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 1752-amino-N-((1S,2S)-2-((4′-((3,3-difluoropiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1762-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methyl-piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 1772-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example178 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-phenyl-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 1792-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 1802-amino-N-((1S,2S)-2-((4′-((4-hydroxypiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1812-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1822-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 1832-amino-N-((1S,2S)-2-((4′-((4-ethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example1842-amino-N-((1S,2S)-2-((4′-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1852-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((R)-3-methyl-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 1862-amino-N-((1S,2S)-2-((4′-(((R)-3,4-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1872-amino-N-((1S,2S)-2-((4′-(((R)-2,4-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1882-amino-N-((1S,2S)-2-((4′-((3-ethyl-4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1892-amino-N-((1S,2S)-2-((4′-((cis-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1902-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 1912-amino-N-((1S,2S)-2-((4′-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1922-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 1932-amino-N-((1S,2S)-2-((4′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1943-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-pyrazine-2-carboxamide Example 1952-amino-N-((1S,2S)-2-((3′-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1962-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 1972-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)nicotinamide Example 1982-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-methyl-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)nicotinamide Example 1992-amino-N-((1S,2S)-2-((3′-hydroxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2002-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methyl-piperazin-1-yl)methyl)-3′-nitro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 2012-amino-N-((1S,2S)-2-((3′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2022-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2032-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methyl-piperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamideExample 2042-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methyl-piperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamideExample 2052-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2062-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2072-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoro-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example208 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methyl-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 2092-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 2102-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2112-amino-N-((1S,2S)-2-((4′-(1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethyl-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2122-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2132-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example2142-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(4-methyl-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 2152-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((S)-1-(4-methyl-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 2162-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methyl-piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 2172-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methyl-piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 2182-amino-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2192-amino-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2202-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)-cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2212-amino-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2226-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 2236-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 2246-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 2256-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 2266-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2276-amino-6′-fluoro-N-((1S,2S)-2-((4′-4((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2286-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2296-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2306-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 2312-amino-5-chloro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2322-amino-5-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2332-amino-5-cyano-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2342-amino-6-chloro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2352-amino-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 2366-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2376-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2386-amino-2′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 2392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methyl-piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 2402-amino-N-((1S,2S)-2-((4′-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 241 methyl2-(4-((4′-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamido)cyclopentyl)oxy)methyl)-[1,1′-biphenyl]-4-yl)methyl)piperidin-1-yl)acetate Example 2422-amino-N-((1S,2S)-2-((4′-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 2432-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methyl-piperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide Example 2442-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2452-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example2462-amino-N-((1S,2S)-2-((4′-(3-(dimethylamino)propoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example247 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methyl-piperidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 2482-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)prop-1-yn-1-yl)benzyl)-oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2492-amino-N-((1S,2S)-2-((4-(4-hydroxybut-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2502-amino-N-((1S,2S)-2-((4-(5-hydroxypent-1-yn-1-yl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2512-amino-N-((1S,2S)-2-((4-(6-hydroxyhex-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2522-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(4-(4-methyl-piperazin-1-yl)but-1-yn-1-yl)benzyl)oxy)cyclopentyl)nicotinamide Example2532-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 2542-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2552-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2572-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2582-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-yl-methyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2592-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2602-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 2612-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2622-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)-amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2632-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2642-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)-nicotinamide Example 2652-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)-nicotinamide Example 2662-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)-phenyl)nicotinamide Example 2672-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)-nicotinamide Example 2682-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 2696-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-bipyridine]-5-carboxamide Example 2702-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methyl-piperazin-1-yl)methyl)phenyl)nicotinamide Example 2712-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methyl-piperazine-1-carbonyl)phenyl)nicotinamide Example 2722-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 2732-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methyl-piperazin-1-yl)methyl)phenyl)nicotinamide Example 2742-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 2752-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example 2762-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methyl-piperazine-1-carbonyl)phenyl)nicotinamide Example 2772-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 2782-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide Example 2792-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamide Example 2802-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 2812-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example2822-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamide Example 2832-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 2842-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 2852-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethyl-benzyl)oxy)cyclopentyl)nicotinamide Example 2862-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethyl-benzyl)oxy)cyclopentyl)nicotinamide Example 2872-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamide Example 2882-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide Example289 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 2902-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide Example 2912-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 2922-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 2932-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide Example 2946-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2′-methoxy-[3,3′-bipyridine]-5-carboxamide Example 2952-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide Example 2962-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxy-phenyl)nicotinamide Example 2972-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)nicotinamide Example 2982-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methyl-sulfonamido)phenyl)nicotinamide Example 2992-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxy-methyl)phenyl)nicotinamide Example 3002-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide Example 3012-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxypropyl)phenyl)nicotinamide Example 3022-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide Example 3032-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 3042-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamide Example 3053-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acid Example 3064-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)-pyridin-3-yl)-2-methylbenzoic acid Example 3072-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)nicotinamide Example 3083-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoic acid Example 3093-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoic acid Example 3102-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example3112-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 3122-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3132-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxy-methyl)phenyl)nicotinamide Example 3142-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formyl-phenyl)nicotinamide Example 315 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidExample 3163-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)phenyl)propanoic acid Example 3172-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxy-phenyl)nicotinamide Example 3182-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 3192-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamide Example 3202-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 3216-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-bipyridine]-5-carboxamide Example 3222-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidExample 3232-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamide Example 3242-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamide Example 3252-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example326 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamide Example 3272-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3282-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 3292-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamide Example 3302-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example3312-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3322-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3332-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamide Example 3342-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)nicotinamide Example 3352-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)-nicotinamide Example 3362-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamide Example 3372-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3382-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3392-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3402-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3412-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3422-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3432-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3442-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example345 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide Example 3462-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3472-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3482-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3492-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3502-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 3512-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamide Example 3522-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamide Example 3532-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)nicotinamide Example 354amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamide Example 3552-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 3562-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 3572-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide Example3582-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 3592-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example 3602-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example3613-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 362(S)-3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide Example 3632-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3642-amino-5-(3,4-difluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3652-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamideExample 3662-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-nicotinamide Example 3672-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamideExample 3682-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-nicotinamide Example 3692-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4′-((4-methyl-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide Example 3702-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide Example 3712-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide Example 3722-amino-5-(4-hydroxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3732-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideExample 3742-amino-5-methyl-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 3756-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 3762-amino-5-(4-methoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3776-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamide Example 3782-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-nicotinamide Example 3792-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamideExample 3802-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 3812-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamide Example 3822-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3832-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example3846-amino-2′,6′-difluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamideExample 3852-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide Example3866-amino-6′-fluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideExample 3872-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)-nicotinamide Example 3882-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 3892-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 3902-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 3912-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 3922-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamide Example 3934-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoic acid Example 3942-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamide Example 3956-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4′-bipyridine]-5-carboxamide Example 3966-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3′-bipyridine]-5-carboxamide Example 3972-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamide Example 3982-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamide Example 3992-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamide Example 4002-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4012-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamide Example 4022-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamide Example 4035-([1,1′-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4042-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4052-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4062-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamide Example 4072-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4082-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamide Example 4092-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide Example 4102-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamide Example 4112-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4122-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 4132-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 4142-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4152-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4162-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4172-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4182-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4192-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 4202-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide Example 4212-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonyl)phenyl)nicotinamide Example 4222-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4232-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide Example 4242-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 4252-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 4262-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4272-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4282-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideExample 4292-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4302-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4312-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4322-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4332-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example434 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methyl-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide Example 4352-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4362-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamid Example 4372-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 4382-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-(1-(4-methyl-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide Example 4392-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide Example 4402-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4412-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4422-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 4432-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4442-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4452-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4462-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4472-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4482-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4492-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methyl-piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-yl)nicotinamide Example 4502-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-(2-(4-methyl-piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4512-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide Example 4522-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4532-amino-N-((3S,4R)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4542-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamideExample 4552-amino-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 4562-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamide Example 4572-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(phenylamino)nicotinamide; and Example 4582-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)nicotinamide.


5. A pharmaceutical composition comprising the heterocyclic compound,the stereoisomer thereof, the enantiomer thereof, or thepharmaceutically acceptable salt thereof according to claim 1 togetherwith a pharmaceutically acceptable carrier.
 6. The pharmaceuticalcomposition of claim 5, wherein the composition comprises, as an activeingredient, the heterocyclic compound, the stereoisomer thereof, theenantiomer thereof, or the pharmaceutically acceptable salt thereof inan amount effective for prevention or treatment of a disease that isinfluenced by inhibition of Mer kinase.
 7. The pharmaceuticalcomposition of claim 6, wherein the disease which is influenced byinhibition of Mer kinase is cancer or an immune-related disease.
 8. Thepharmaceutical composition of claim 7, wherein the cancer is selectedfrom the group consisting of: glioma, gliosarcoma, anaplasticastrocytoma, medulloblastoma, lung cancer, small cell lung carcinoma,cervical carcinoma, colon cancer, rectal cancer, chordoma, throatcancer, Kaposi's sarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, colorectal cancer, endometrium cancer,ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renalcell carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma,seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladdercarcinoma, angiosarcoma, endotheliosarcoma, adenocarcinoma, sweat glandcarcinoma, sebaceous gland sarcoma, papillary sarcoma, papillaryadenosarcoma, cystadenosarcoma, bronchogenic carcinoma, medullarycarcinoma, mastocytoma, mesotheliorma, synovioma, melanoma,leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma,oligodentroglioma, acoustic neuroma, hemangioblastoma, meningioma,pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma,embryonal carcinoma, squamous cell carcinoma, base cell carcinoma,fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, leukemia and metastatic lesions secondary to theseprimary tumors.
 9. The pharmaceutical composition of claim 7, whereinthe immune-related disease is selected from the group consisting ofinfection and sepsis.
 10. A method of treating or preventing animmune-related disease or cancer, the method comprising administering toa mammal in need thereof compositions comprising, as active ingredients,the heterocyclic compounds, isomers thereof or pharmaceuticallyacceptable salts thereof according to claim
 1. 11. The method of claim10, wherein the mammal is a human.